A tribute to Terry Strom J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-05 Laurence A. Turka; Manikkam Suthanthiran
Terry Barton Strom, a giant in the field of transplantation immunology, died in Boston on December 20th, surrounded by friends and family, at the age of 76. He will be remembered by all whose path he crossed for his intellect and persona. Terry grew up on the South Side of Chicago (more on that later) and went on to start his undergraduate studies at the University of Illinois. He entered medical school at the University of Illinois after his junior year, and — having never satisfied the foreign language requirement of the University — could not be awarded a bachelor’s degree. Thus, he was one of the rare physicians and academicians to have never graduated from college (although Harvard later awarded him a degree). This certainly did not hold him back. Following medical school, Terry was an intern in medicine at the University of Illinois and was then recruited to be a senior resident in medicine at the Beth Israel Hospital, after which he was renal fellow at the Peter Bent Brigham Hospital. On the completion of his clinical training, he worked in the lab of gentleman-scholar Charles (Bernie) Carpenter, entering and helping define the then nascent field of transplantation immunology. He was among the first and most distinguished of a long line of scientists to emerge from the Carpenter laboratory, the authors of this tribute include. Following his formal laboratory training, Terry’s initial faculty appointment was at the Pent Brigham Hospital, and he later moved across the street to the Beth Israel Deaconess Hospital, where he stayed for the rest of his distinguished career. He established the Department of Immunology, rose through the ranks to become a Professor of Medicine and Surgery at Harvard Medical School, trained and mentored many fine scientists, and made numerous discoveries that have improved the lives of transplant recipients as well as patients with autoimmune diseases. A prolific author of almost 500 original articles, Terry’s seminal studies were models of clarity. For example, one of his early publications in the Proceedings of the National Academy of Sciences was the first description of cholinergic agents augmenting lymphocyte-mediated cytotoxicity (LMC), an effector mechanism central to the rejection of histoincompatible grafts (1). This original observation was rapidly amplified within a year by a publication in Science regarding the importance of microtubule integrity in LMC (2) and a publication in the Journal of Experimental Medicine regarding the counter-regulatory role of cyclic nucleotides on LMC (3). Yet another novel observation was the finding that insulin augmented LMC (published in Science) (4) followed by the demonstration of insulin receptors on alloimmune T cells (reported in the JCI) (5) that functioned as markers of activated T cells and B cells (reported in Nature) (6). These early studies foreshadow our current interest in T cell metabolism and identification of antigen-reactive cells via activation markers. Terry’s preclinical investigations helped advance IL-2 receptor α (CD25) as a suitable target to prevent rejection in organ graft recipients, an idea that has been successfully translated to the clinic. Terry’s incisive studies have not only enabled clinical application of monoclonal antibodies, but have also improved our understanding of several immunosuppressive drugs currently used in the transplantation arena, including cyclosporine, glucocorticoids, and mTOR inhibitors. Ever alert to promising inventions, Terry adopted the PCR assay to pioneer the characterization of intragraft gene expression patterns in preclinical transplantation models and, subsequently, in rejecting human allografts. In the spirit of “A man should look for what is and not for what he thinks should be,” Terry and his talented team unhesitatingly reported that acute rejection, previously considered a consequence primarily of graft-destructive immunity, is unexpectedly associated with the development of suppressor cells. Finally, a logical extension of this technology led to the exploration of peripheral blood gene expression patterns as biomarkers of allograft status. Thus, Terry’s lab had a transformative impact in our understanding of transplant rejection and our goal of achieving transplant tolerance. In recognition of his seminal contributions, Terry was honored by numerous awards, including election to the ASCI (almost 40 years ago), the Homer Smith Award of the American Society of Nephrology, the Starzl Prize in Surgery and Immunology, and the Established Investigator Award and Distinguished Achievement award, both from the American Society of Transplantation (AST). He is a past president of the AST and the founding president of Clinical Immunology Society. In recognition of his mentorship, Terry was awarded the AST Mentoring Award. Indeed, Terry is the recipient of every honor the AST can bestow on a transplant physician scientist. We had the privilege of collaborating with Terry in some of these studies and, like others who worked with him, admired his intellectual creativity and envied his ability to think outside the box. And not surprisingly, he was beloved by his patients. The accomplishments above are truly impressive, but what those fortunate enough to know Terry will remember even more is his outsized personality. Terry was a character — there is no better word. He exuded boyish charm. With his full head of hair, gap-toothed smile, and large (6’4”) stature, he was a legend (see accompanying image). Befittingly, his son called him “Big T” and his brother called him “Zeus.” Growing up in a rough-and-tumble Polish neighborhood on Chicago’s South Side, Terry was the big Jewish kid — a target — but he learned to “give as good as he got.” He was also, by all accounts, a bad-ass kid. Those who had the privilege of knowing Terry as an adult will probably not be surprised that he was expelled from Hebrew school for throwing eggs at the rabbi. Or that, while serving in the Air Force (and it is truly hard to imagine Terry in the military), he did volunteer work for the Black Panthers. However, they might be surprised to learn that he had a life-time ban at the famed Drake Hotel on Michigan Avenue for serially crashing weddings, culminating in a food fight involving the wedding cake. At least that’s the legend, but if you knew Terry, you knew that it was eminently believable. And no one who knew Terry would be surprised that he was tremendously proud of these stories. He reveled in rising from humble beginnings to the peak of a lofty profession. And he loved being a rebel. In addition to his intellectual talents, Terry was a gifted athlete. A rising high school football player, he and Dick Butkus were featured together in the local news. But two life-threatening subdural hematomas put an end to his athletic career. After recovering from surgery and emerging from a coma, his family and friends found him a changed man, no longer the prankster of earlier days. His lifelong friend Jon Borus refers to it as a “therapeutic/traumatic injury,” one that enabled him to focus his talents — and we are all better off for it. While no longer a competitive athlete, Terry remained fiercely competitive. His children recall races in the park and hard-fought basketball games in the driveway that were always fun but were also training for life, where someone was always bigger and better, and you had better get used to it. In the halcyon days of postgraduate training when every minute of fellowship did not have be accounted for, one of the authors (identity intentionally concealed!) of this piece recalls very fondly spending several afternoons in Terry’s club playing what started as a friendly game of tennis and ending in a highly competitive brawl. A devoted fan, Terry thrilled in the success of Boston teams, but especially the Celtics. Among Terry’s many other hobbies, his love of wine and wine-making particularly stand out. He was especially proud that a dessert wine he had made one year with purchased grapes found its way onto the wine list of one of Boston’s finest restaurants. His friends also remember an exceedingly generous man — one who would take you into his home in hard times and be with you when you needed him. An event that exemplifies Terry’s utmost humanism is one personally experienced by one of the authors of this tribute (M. Suthanthiran). “On the first day of my transplant fellowship, I had to call Terry, my transplant attending, to seek his permission to return to Detroit Children’s Hospital to attend to my 9-year-old nephew, who had just been readmitted for a postoperative complication following total correction of Tetralogy of Fallot,” Suthanthiran said. “I was deeply concerned about making this request on my very first day of fellowship. Despite the unanticipated burden imposed on him by the sudden absence of the renal fellow on a very busy transplant service, Terry, without any hesitation whatsoever, said in the most caring voice, ‘Please, go and come back only when you feel comfortable.’” Terry’s death was due to complications of an allogeneic stem cell transplant he received as part of his treatment for myelofibrosis (itself occurring as a complication of an earlier, and curative, autologous stem cell transplant for myeloma). He could have opted for maintenance transfusions but, instead, chose a riskier but potentially curative treatment. It reflected his tremendous optimism and joie de vivre, which were palpable to all he knew. One only had to be lucky enough to enjoy a meal or drink with friends at Terry and his wife Margot’s home in Brookline (where they lived together for almost 50 years) to see his spirit in action. In many religions and belief systems, there is a variation of the aphorism that one must leave the world better than one finds it. Terry Strom — our brilliant mentor and dear friend — has most certainly not only enriched the field of immunobiology and transplantation, but also stimulated each of us to be better individuals. Terry Strom was blessed with a wonderful family. The authors thank them — in particular his wife, Margot, and children, Adam and Rachel, — for sharing their memories of Terry. We join them in mourning his passing; we are all poorer for it. Footnotes Reference information: J Clin Invest. 2018;128(3):891–892. https://doi.org/10.1172/JCI99905. References Strom TB, Deisseroth A, Morganroth J, Carpenter CB, Merrill JP. Alteration of the cytotoxic action of sensitized lymphocytes by cholinergic agents and activators of adenylate cyclase. Proc Natl Acad Sci U S A. 1972;69(10):2995–2999.View this article via: PubMedCrossRefGoogle Scholar Strom TB, Garovoy MR, Carpenter DB, Merrill JP. Microtubule function in immune and nonimmune lymphocyte-mediated cytotoxicity. Science. 1973;181(4095):171–173.View this article via: PubMedCrossRefGoogle Scholar Strom TB, Carpenter CB, Garovoy MR, Austen KF, Merrill JP, Kaliner M. The modulating influence of cyclic nucleotides upon lymphocyte-mediated cytotoxicity. J Exp Med. 1973;138(2):381–393.View this article via: PubMedCrossRefGoogle Scholar Strom TB, Bear RA, Carpenter CB. Insulin-induced augmentation of lymphocyte-mediated cytotoxicity. Science. 1975;187(4182):1206–1208.View this article via: PubMedCrossRefGoogle Scholar Helderman JH, Strom TB. Emergence of insulin receptors upon alloimmune T cells in the rat. J Clin Invest. 1977;59(2):338–344.View this article via: JCIPubMedCrossRefGoogle Scholar Helderman JH, Strom TB. Specific insulin binding site on T and B lymphocytes as a marker of cell activation. Nature. 1978;274(5666):62–63.View this article via: PubMedCrossRefGoogle Scholar
Cardiovascular outcome trials of diabetes drugs: lessons learned J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-12 Simeon I. Taylor; Bruce R. Leslie
Excerpt: Diabetes mellitus is a risk factor for coronary heart disease, ischemic stroke, and peripheral arterial occlusion (macrovascular disease), as well as chronic kidney disease, neuropathy, and retinopathy (microvascular disease). Antihyperglycemic treatments reduce the risk of microvascular conditions, but their effect on macrovascular events is uncertain (1, 2). Years ago, the...
Newly found arsons ignite the fire of gut GVHD J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-29 Defu Zeng
Acute graft-versus-host disease (GVHD) in the gut is common following hematopoetic cell transplantation (HCT) and is associated with high mortality. However, it remains unclear whether Th1 or Th17 CD4+ T cells can initiate acute gut GVHD. In this issue of the JCI, Ullrich and colleagues identified a subset of CD4+ T cells that express high levels of IL-7Rα and granulocyte-macrophage CSF (IL-7RαhiGM-CSF+) cells that are involved in the induction of acute gut GVHD in murine models. The IL-7RαhiGM-CSF+ effector memory cells were BATF dependent, RORγt independent, produced large amounts of GM-CSF and IFN-γ, and released little IL-17. CD4+IL-7RαhiGM-CSF+ cells were not classical Th17 cells but had more of a Th1-like phenotype, despite their dependence on BATF. This work suggests that targeting the IL-7R/BATF/GM-CSF axis has therapeutic potential for treating acute gut GVHD.
Hypothalamic loss of Snord116 and Prader-Willi syndrome hyperphagia: the buck stops here? J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-29 Juan A. Rodriguez; Jeffrey M. Zigman
Hyperphagia and obesity are the best-known manifestations of Prader-Willi syndrome (PWS) and are responsible for most of the overall morbidity and mortality associated with the disease. Yet these PWS symptoms remain poorly understood and without effective pharmacologic therapies. Mouse models attempting to recapitulate both the genetic alterations and marked hyperphagia plus obesity of PWS have been enigmatic, leading to skepticism about the use of mouse models to investigate PWS. In this issue of the JCI, Polex-Wolf and colleagues challenge the skeptics by successfully inducing hyperphagia following bilateral mediobasal hypothalamic deletion of the Snord116 gene from adult mice. Obesity also resulted, although only in a subset of mice. While this approach represents an exciting advance, highlighting a pathologic effect of loss of mediobasal hypothalamic Snord116 expression on the development of PWS’s hallmark symptoms, the variability in the body-weight and body composition responses to this site-selective gene deletion raises several questions.
Claudin-18: unexpected regulator of lung alveolar epithelial cell proliferation J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-05 Darrell N. Kotton
Claudin 18 (CLDN18) is a tight junction protein that is highly expressed in the lung. While mice lacking CLDN18 exhibit the expected loss of epithelial integrity in the lung, these animals also have unexpectedly large lungs. In this issue of the JCI, Zhou, Flodby, and colleagues reveal that the increased lung size of Cldn18–/– mice is the result of increased type 2 alveolar epithelial (AT2) cell proliferation. This increase in proliferation was shown to be driven by translocation of the transcriptional regulator Yes-associated protein (YAP) to the nucleus and subsequent induction of proliferative pathways. CLDN18-deficent mice also had increased frequency of lung adenocarcinomas. Together, the results of this study advance our understanding of the mechanisms that likely regulate homeostasis of the normal lung as well as promote the proliferative state of malignant cells found in lung adenocarcinomas thought to originate from AT2 cells.
All plugged up — noninvasive mucus score to assess airway dysfunction in asthma J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-05 Steve N. Georas
Asthma is remarkably heterogeneous, and there are multiple underlying inflammatory pathways and structural airway abnormalities that lead to symptomatic disease. Consequently, a current challenge in the field is to precisely characterize different types of asthma, with the goal of developing personalized approaches to therapy. In the current issue of the JCI, Dunican et al. developed a noninvasive way to assess airway dysfunction in asthma by measuring mucus accumulation using multidetector computed tomography (MDCT) and found that mucus plugging of small airways was remarkably common in subjects with severe asthma. This work highlights the importance of noninvasive imaging approaches in defining specific asthma subsets and guiding targeted therapies.
Alternative macrophages in atherosclerosis: not always protective! J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-19 Benoit Pourcet; Bart Staels
Atherosclerosis is a chronic inflammatory disease of the vasculature that is initiated by cholesterol deposition into the arterial wall, which triggers the infiltration of immune and inflammatory cells, including monocytes and macrophages. As atherosclerotic plaques progress, localized hypoxia promotes compensatory angiogenesis from the vasa vasorum. Immature neovessels are prone to leakage, thus destabilizing the plaque and leading to intraplaque hemorrhage. Macrophages with different phenotypes, ranging from classical inflammatory subtypes to alternatively activated antiinflammatory macrophages, have been identified in atherosclerotic lesions. Antiinflammatory hemoglobin-scavenging CD163+ macrophages are present in neovessel- and hemorrhage-rich areas; however, the role of these macrophages in atherogenesis has been unclear. In this issue of the JCI, Guo, Akahori, and colleagues show that CD163+ macrophages promote angiogenesis, vessel permeability, and leucocyte infiltration in human and mouse atherosclerotic lesions through a mechanism involving hemoglobin:haptoglobin/CD163/HIF1α-mediated VEGF induction. This study thus identifies proatherogenic properties of CD163+ macrophages, which previously were thought to be beneficial.
SCN5A: the greatest HITS collection J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-19 David S. Park; Glenn I. Fishman
Heart failure (HF) has been referred to as the cardiovascular epidemic of our time. Understanding the molecular determinants of HF disease progression and mortality risk is of utmost importance. In this issue of the JCI, Zhang et al. uncover an important link between clinical HF mortality risk and a common variant that regulates SCN5A expression through microRNA-dependent (miR-dependent)mechanisms. They also demonstrate that haploinsufficiency of SCN5A is associated with increased accumulation of reactive oxygen species (ROS) in a genetically engineered murine model. Their data suggest that even modest depression of SCN5A expression may promote pathologic cardiac remodeling and progression of HF.
BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-29 Evelyn Ullrich; Benjamin Abendroth; Johanna Rothamer; Carina Huber; Maike Büttner-Herold; Vera Buchele; Tina Vogler; Thomas Longerich; Sebastian Zundler; Simon Völkl; Andreas Beilhack; Stefan Rose-John; Stefan Wirtz; Georg F. Weber; Sakhila Ghimire; Marina Kreutz; Ernst Holler; Andreas Mackensen; Markus F. Neurath; Kai Hildner
Acute graft-versus-host disease (GVHD) represents a severe, T cell–driven inflammatory complication following allogeneic hematopoietic cell transplantation (allo-HCT). GVHD often affects the intestine and is associated with a poor prognosis. Although frequently detectable, proinflammatory mechanisms exerted by intestinal tissue–infiltrating Th cell subsets remain to be fully elucidated. Here, we show that the Th17-defining transcription factor basic leucine zipper transcription factor ATF-like (BATF) was strongly regulated across human and mouse intestinal GVHD tissues. Studies in complete MHC-mismatched and minor histocompatibility–mismatched (miHA-mismatched) GVHD models revealed that BATF-expressing T cells were functionally indispensable for intestinal GVHD manifestation. Mechanistically, BATF controlled the formation of colon-infiltrating, IL-7 receptor–positive (IL-7R+), granulocyte-macrophage colony-stimulating factor–positive (GM-CSF+), donor T effector memory (Tem) cells. This T cell subset was sufficient to promote intestinal GVHD, while its occurrence was largely dependent on T cell–intrinsic BATF expression, required IL-7–IL-7R interaction, and was enhanced by GM-CSF. Thus, this study identifies BATF-dependent pathogenic GM-CSF+ effector T cells as critical promoters of intestinal inflammation in GVHD and hence putatively provides mechanistic insight into inflammatory processes previously assumed to be selectively Th17 driven.
Microglia are required for protection against lethal coronavirus encephalitis in mice J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-29 D. Lori Wheeler; Alan Sariol; David K. Meyerholz; Stanley Perlman
Recent findings have highlighted the role of microglia in orchestrating normal development and refining neural network connectivity in the healthy CNS. Microglia are not only vital cells in maintaining CNS homeostasis, but also respond to injury, infection, and disease by undergoing proliferation and changes in transcription and morphology. A better understanding of the specific role of microglia in responding to viral infection is complicated by the presence of nonmicroglial myeloid cells with potentially overlapping function in the healthy brain and by the rapid infiltration of hematopoietic myeloid cells into the brain in diseased states. Here, we used an inhibitor of colony-stimulating factor 1 receptor (CSF1R) that depletes microglia to examine the specific roles of microglia in response to infection with the mouse hepatitis virus (MHV), a neurotropic coronavirus. Our results show that microglia were required during the early days after infection to limit MHV replication and subsequent morbidity and lethality. Additionally, microglia depletion resulted in ineffective T cell responses. These results reveal nonredundant, critical roles for microglia in the early innate and virus-specific T cell responses and for subsequent host protection from viral encephalitis.
Factor XII and uPAR upregulate neutrophil functions to influence wound healing J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-29 Evi X. Stavrou; Chao Fang; Kara L. Bane; Andy T. Long; Clément Naudin; Erdem Kucukal; Agharnan Gandhi; Adina Brett-Morris; Michele M. Mumaw; Sudeh Izadmehr; Alona Merkulova; Cindy C. Reynolds; Omar Alhalabi; Lalitha Nayak; Wen-Mei Yu; Cheng-Kui Qu; Howard J. Meyerson; George R. Dubyak; Umut A. Gurkan; Marvin T. Nieman; Anirban Sen Gupta; Thomas Renné; Alvin H. Schmaier
Coagulation factor XII (FXII) deficiency is associated with decreased neutrophil migration, but the mechanisms remain uncharacterized. Here, we examine how FXII contributes to the inflammatory response. In 2 models of sterile inflammation, FXII-deficient mice (F12–/–) had fewer neutrophils recruited than WT mice. We discovered that neutrophils produced a pool of FXII that is functionally distinct from hepatic-derived FXII and contributes to neutrophil trafficking at sites of inflammation. FXII signals in neutrophils through urokinase plasminogen activator receptor–mediated (uPAR-mediated) Akt2 phosphorylation at S474 (pAktS474). Downstream of pAkt2S474, FXII stimulation of neutrophils upregulated surface expression of αMβ2 integrin, increased intracellular calcium, and promoted extracellular DNA release. The sum of these activities contributed to neutrophil cell adhesion, migration, and release of neutrophil extracellular traps in a process called NETosis. Decreased neutrophil signaling in F12–/– mice resulted in less inflammation and faster wound healing. Targeting hepatic F12 with siRNA did not affect neutrophil migration, whereas WT BM transplanted into F12–/– hosts was sufficient to correct the neutrophil migration defect in F12–/– mice and restore wound inflammation. Importantly, these activities were a zymogen FXII function and independent of FXIIa and contact activation, highlighting that FXII has a sophisticated role in vivo that has not been previously appreciated.
Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-29 Joseph Polex-Wolf; Brian Y.H. Lam; Rachel Larder; John Tadross; Debra Rimmington; Fàtima Bosch; Verónica Jiménez Cenzano; Eduard Ayuso; Marcella K.L. Ma; Kara Rainbow; Anthony P. Coll; Stephen O’Rahilly; Giles S.H. Yeo
Profound hyperphagia is a major disabling feature of Prader-Willi syndrome (PWS). Characterization of the mechanisms that underlie PWS-associated hyperphagia has been slowed by the paucity of animal models with increased food intake or obesity. Mice with a microdeletion encompassing the Snord116 cluster of noncoding RNAs encoded within the Prader-Willi minimal deletion critical region have previously been reported to show growth retardation and hyperphagia. Here, consistent with previous reports, we observed growth retardation in Snord116+/–P mice with a congenital paternal Snord116 deletion. However, these mice neither displayed increased food intake nor had reduced hypothalamic expression of the proprotein convertase 1 gene PCSK1 or its upstream regulator NHLH2, which have recently been suggested to be key mediators of PWS pathogenesis. Specifically, we disrupted Snord116 expression in the mediobasal hypothalamus in Snord116fl mice via bilateral stereotaxic injections of a Cre-expressing adeno-associated virus (AAV). While the Cre-injected mice had no change in measured energy expenditure, they became hyperphagic between 9 and 10 weeks after injection, with a subset of animals developing marked obesity. In conclusion, we show that selective disruption of Snord116 expression in the mediobasal hypothalamus models the hyperphagia of PWS.
Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-05 Beiyun Zhou; Per Flodby; Jiao Luo; Dan R. Castillo; Yixin Liu; Fa-Xing Yu; Alicia McConnell; Bino Varghese; Guanglei Li; Nyam-Osor Chimge; Mitsuhiro Sunohara; Michael N. Koss; Wafaa Elatre; Peter Conti; Janice M. Liebler; Chenchen Yang; Crystal N. Marconett; Ite A. Laird-Offringa; Parviz Minoo; Kunliang Guan; Barry R. Stripp; Edward D. Crandall; Zea Borok
Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony-forming efficiency (CFE) of Cldn18–/– AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, Cldn18–/– mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury.
Randomized, controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-05 Chuang-Wei Wang; Lan-Yan Yang; Chun-Bing Chen; Hsin-Chun Ho; Shuen-Iu Hung; Chih-Hsun Yang; Chee-Jen Chang; Shih-Chi Su; Rosaline Chung-Yee Hui; See-Wen Chin; Li-Fang Huang; Yang Yu-Wei Lin; Wei-Yang Chang; Wen-Lang Fan; Chin-Yi Yang; Ji-Chen Ho; Ya-Ching Chang; Chun-Wei Lu; Wen-Hung Chung; and the Taiwan Severe Cutaneous Adverse Reaction (TSCAR) Consortium
BACKGROUND. Cytotoxic T lymphocyte–mediated (CTL-mediated) severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but life-threatening adverse reactions commonly induced by drugs. Although high levels of CTL-associated cytokines, chemokines, or cytotoxic proteins, including TNF-α and granulysin, were observed in SJS-TEN patients in recent studies, the optimal treatment for these diseases remains controversial. We aimed to evaluate the efficacy, safety, and therapeutic mechanism of a TNF-α antagonist in CTL-mediated SCARs.
Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-05 Eleanor M. Dunican; Brett M. Elicker; David S. Gierada; Scott K. Nagle; Mark L. Schiebler; John D. Newell; Wilfred W. Raymond; Marrah E. Lachowicz-Scroggins; Selena Di Maio; Eric A. Hoffman; Mario Castro; Sean B. Fain; Nizar N. Jarjour; Elliot Israel; Bruce D. Levy; Serpil C. Erzurum; Sally E. Wenzel; Deborah A. Meyers; Eugene R. Bleecker; Brenda R. Phillips; David T. Mauger; Erin D. Gordon; Prescott G. Woodruff; Michael C. Peters; John V. Fahy; The National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP)
BACKGROUND. The link between mucus plugs and airflow obstruction has not been established in chronic severe asthma, and the role of eosinophils and their products in mucus plug formation is unknown.
Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-05 Sun-Hye Jeong; Han-Byul Kim; Min-Chul Kim; Ji-min Lee; Jae Ho Lee; Jeong-Hwan Kim; Jin-Woo Kim; Woong-Yang Park; Seon-Young Kim; Jae Bum Kim; Haeryoung Kim; Jin-Man Kim; Hueng-Sik Choi; Dae-Sik Lim
Nonalcoholic fatty liver disease (NAFLD) is a major risk factor for liver cancer; therefore, its prevention is an important clinical goal. Ablation of phosphatase and tensin homolog (PTEN) or the protein kinase Hippo signaling pathway induces liver cancer via activation of AKT or the transcriptional regulators YAP/TAZ, respectively; however, the potential for crosstalk between the PTEN/AKT and Hippo/YAP/TAZ pathways in liver tumorigenesis has thus far remained unclear. Here, we have shown that deletion of both PTEN and SAV1 in the liver accelerates the development of NAFLD and liver cancer in mice. At the molecular level, activation of YAP/TAZ in the liver of Pten–/– Sav1–/– mice amplified AKT signaling through the upregulation of insulin receptor substrate 2 (IRS2) expression. Both ablation of YAP/TAZ and activation of the Hippo pathway could rescue these phenotypes. A high level of YAP/ TAZ expression was associated with a high level of IRS2 expression in human hepatocellular carcinoma (HCC). Moreover, treatment with the AKT inhibitor MK-2206 or knockout of IRS2 by AAV-Cas9 successfully repressed liver tumorigenesis in Pten–/– Sav1–/– mice. Thus, our findings suggest that Hippo signaling interacts with AKT signaling by regulating IRS2 expression to prevent NAFLD and liver cancer progression and provide evidence that impaired crosstalk between these 2 pathways accelerates NAFLD and liver cancer.
Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-05 Carly A. Dillen; Bret L. Pinsker; Alina I. Marusina; Alexander A. Merleev; Orly N. Farber; Haiyun Liu; Nathan K. Archer; Da B. Lee; Yu Wang; Roger V. Ortines; Steven K. Lee; Mark C. Marchitto; Shuting S. Cai; Alyssa G. Ashbaugh; Larissa S. May; Steven M. Holland; Alexandra F. Freeman; Loren G. Miller; Michael R. Yeaman; Scott I. Simon; Joshua D. Milner; Emanual Maverakis; Lloyd S. Miller
The mechanisms that mediate durable protection against Staphylococcus aureus skin reinfections are unclear, as recurrences are common despite high antibody titers and memory T cells. Here, we developed a mouse model of S. aureus skin reinfection to investigate protective memory responses. In contrast with WT mice, IL-1β–deficient mice exhibited poor neutrophil recruitment and bacterial clearance during primary infection that was rescued during secondary S. aureus challenge. The γδ T cells from skin-draining LNs utilized compensatory T cell–intrinsic TLR2/MyD88 signaling to mediate rescue by trafficking and producing TNF and IFN-γ, which restored neutrophil recruitment and promoted bacterial clearance. RNA-sequencing (RNA-seq) of the LNs revealed a clonotypic S. aureus–induced γδ T cell expansion with a complementarity-determining region 3 (CDR3) aa sequence identical to that of invariant Vγ5+ dendritic epidermal T cells. However, this T cell receptor γ (TRG) aa sequence of the dominant CDR3 sequence was generated from multiple gene rearrangements of TRGV5 and TRGV6, indicating clonotypic expansion. TNF- and IFN-γ–producing γδ T cells were also expanded in peripheral blood of IRAK4-deficient humans no longer predisposed to S. aureus skin infections. Thus, clonally expanded γδ T cells represent a mechanism for long-lasting immunity against recurrent S. aureus skin infections.
Physiological genomics identifies genetic modifiers of long QT syndrome type 2 severity J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-12 Sam Chai; Xiaoping Wan; Angelina Ramirez-Navarro; Paul J. Tesar; Elizabeth S. Kaufman; Eckhard Ficker; Alfred L. George Jr.; Isabelle Deschênes
Congenital long QT syndrome (LQTS) is an inherited channelopathy associated with life-threatening arrhythmias. LQTS type 2 (LQT2) is caused by mutations in KCNH2, which encodes the potassium channel hERG. We hypothesized that modifier genes are partly responsible for the variable phenotype severity observed in some LQT2 families. Here, we identified contributors to variable expressivity in an LQT2 family by using induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) and whole exome sequencing in a synergistic manner. We found that iPSC-CMs recapitulated the clinical genotype-phenotype discordance in vitro. Importantly, iPSC-CMs derived from the severely affected LQT2 patients displayed prolonged action potentials compared with cells from mildly affected first-degree relatives. The iPSC-CMs derived from all patients with hERG R752W mutation displayed lower IKr amplitude. Interestingly, iPSC-CMs from severely affected mutation-positive individuals exhibited greater L-type Ca2+ current. Whole exome sequencing identified variants of KCNK17 and the GTP-binding protein REM2, providing biologically plausible explanations for this variable expressivity. Genome editing to correct a REM2 variant reversed the enhanced L-type Ca2+ current and prolonged action potential observed in iPSC-CMs from severely affected individuals. Thus, our findings showcase the power of combining complementary physiological and genomic analyses to identify genetic modifiers and potential therapeutic targets of a monogenic disorder. Furthermore, we propose that this strategy can be deployed to unravel myriad confounding pathologies displaying variable expressivity.
STAT3/p53 pathway activation disrupts IFN-β–induced dormancy in tumor-repopulating cells J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-12 Yuying Liu; Jiadi Lv; Jinyan Liu; Xiaoyu Liang; Xun Jin; Jing Xie; Le Zhang; Degao Chen; Roland Fiskesund; Ke Tang; Jingwei Ma; Huafeng Zhang; Wenqian Dong; Siqi Mo; Tianzhen Zhang; Feiran Cheng; Yabo Zhou; Qingzhu Jia; Bo Zhu; Yan Kong; Jun Guo; Haizeng Zhang; Zhuo-Wei Hu; Xuetao Cao; F. Xiao-Feng Qin; Bo Huang
Dynamic interaction with the immune system profoundly regulates tumor cell dormancy. However, it is unclear how immunological cues trigger cancer cell–intrinsic signaling pathways for entering into dormancy. Here, we show that IFN-β treatment induced tumor-repopulating cells (TRC) to enter dormancy through an indolamine 2,3-dioxygenase/kynurenine/aryl hydrocarbon receptor/p27–dependent (IDO/Kyn/AhR/p27-dependent) pathway. Strategies to block this metabolic circuitry did not relieve dormancy, but led to apoptosis of dormant TRCs in murine and human melanoma models. Specifically, blocking AhR redirected IFN-β signaling to STAT3 phosphorylation through both tyrosine and serine sites, which subsequently facilitated STAT3 nuclear translocation and subsequent binding to the p53 promoter in the nucleus. Upregulation of p53 in turn disrupted the pentose phosphate pathway, leading to excessive ROS production and dormant TRC death. Additionally, in melanoma patients, high expression of IFN-β correlated with tumor cell dormancy. Identification of this mechanism for controlling TRC dormancy by IFN-β provides deeper insights into cancer-immune interaction and potential new cancer immunotherapeutic modalities.
Disruption of staphylococcal aggregation protects against lethal lung injury J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-12 Jaime L. Hook; Mohammad N. Islam; Dane Parker; Alice S. Prince; Sunita Bhattacharya; Jahar Bhattacharya
Infection by Staphylococcus aureus strain USA300 causes tissue injury, multiorgan failure, and high mortality. However, the mechanisms by which the bacteria adhere to, then stabilize on, mucosal surfaces before causing injury remain unclear. We addressed these issues through the first real-time determinations of USA300-alveolar interactions in live lungs. We found that within minutes, inhaled USA300 established stable, self-associated microaggregates in niches at curved, but not at flat, regions of the alveolar wall. The microaggregates released α-hemolysin toxin, causing localized alveolar injury, as indicated by epithelial dye loss, mitochondrial depolarization, and cytosolic Ca2+ increase. Spread of cytosolic Ca2+ through intercellular gap junctions to adjoining, uninfected alveoli caused pulmonary edema. Systemic pretreatment with vancomycin, a USA300-cidal antibiotic, failed to protect mice infected with inhaled WT USA300. However, vancomycin pretreatment markedly abrogated mortality in mice infected with mutant USA300 that lacked the aggregation-promoting factor PhnD. We interpret USA300-induced mortality as having resulted from rapid bacterial aggregation in alveolar niches. These findings indicate, for the first time to our knowledge, that alveolar microanatomy is critical in promoting the aggregation and, hence, in causing USA300-induced alveolar injury. We propose that in addition to antibiotics, strategies for bacterial disaggregation may constitute novel therapy against USA300-induced lung injury.
Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-12 Naomi Dirckx; Robert J. Tower; Evi M. Mercken; Roman Vangoitsenhoven; Caroline Moreau-Triby; Tom Breugelmans; Elena Nefyodova; Ruben Cardoen; Chantal Mathieu; Bart Van der Schueren; Cyrille B. Confavreux; Thomas L. Clemens; Christa Maes
The skeleton has emerged as an important regulator of systemic glucose homeostasis, with osteocalcin and insulin representing prime mediators of the interplay between bone and energy metabolism. However, genetic evidence indicates that osteoblasts can influence global energy metabolism through additional, as yet unknown, mechanisms. Here, we report that constitutive or postnatally induced deletion of the hypoxia signaling pathway component von Hippel–Lindau (VHL) in skeletal osteolineage cells of mice led to high bone mass as well as hypoglycemia and increased glucose tolerance, not accounted for by osteocalcin or insulin. In vitro and in vivo data indicated that Vhl-deficient osteoblasts displayed massively increased glucose uptake and glycolysis associated with upregulated HIF-target gene expression, resembling the Warburg effect that typifies cancer cells. Overall, the glucose consumption by the skeleton was increased in the mutant mice, as revealed by 18F-FDG radioactive tracer experiments. Moreover, the glycemia levels correlated inversely with the level of skeletal glucose uptake, and pharmacological treatment with the glycolysis inhibitor dichloroacetate (DCA), which restored glucose metabolism in Vhl-deficient osteogenic cells in vitro, prevented the development of the systemic metabolic phenotype in the mutant mice. Altogether, these findings reveal a novel link between cellular glucose metabolism in osteoblasts and whole-body glucose homeostasis, controlled by local hypoxia signaling in the skeleton.
CD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-19 Liang Guo; Hirokuni Akahori; Emanuel Harari; Samantha L. Smith; Rohini Polavarapu; Vinit Karmali; Fumiyuki Otsuka; Rachel L. Gannon; Ryan E. Braumann; Megan H. Dickinson; Anuj Gupta; Audrey L. Jenkins; Michael J. Lipinski; Johoon Kim; Peter Chhour; Paul S. de Vries; Hiroyuki Jinnouchi; Robert Kutys; Hiroyoshi Mori; Matthew D. Kutyna; Sho Torii; Atsushi Sakamoto; Cheol Ung Choi; Qi Cheng; Megan L. Grove; Mariem A. Sawan; Yin Zhang; Yihai Cao; Frank D. Kolodgie; David P. Cormode; Dan E. Arking; Eric Boerwinkle; Alanna C. Morrison; Jeanette Erdmann; Nona Sotoodehnia; Renu Virmani; Aloke V. Finn
Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non–foam cell antiinflammatory macrophage phenotype that was previously considered atheroprotective. Here, we reveal an unexpected but important pathogenic role for these macrophages in atherosclerosis. Using human atherosclerotic samples, cultured cells, and a mouse model of advanced atherosclerosis, we investigated the role of intraplaque hemorrhage on macrophage function with respect to angiogenesis, vascular permeability, inflammation, and plaque progression. In human atherosclerotic lesions, CD163+ macrophages were associated with plaque progression, microvascularity, and a high level of HIF1α and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163+ macrophages. Within these cells, activation of HIF1α via inhibition of prolyl hydroxylases promoted VEGF-mediated increases in intraplaque angiogenesis, vascular permeability, and inflammatory cell recruitment. CD163+ macrophages increased intraplaque endothelial VCAM expression and plaque inflammation. Subjects with homozygous minor alleles of the SNP rs7136716 had elevated microvessel density, increased expression of CD163 in ruptured coronary plaques, and a higher risk of myocardial infarction and coronary heart disease in population cohorts. Thus, our findings highlight a nonlipid-driven mechanism by which alternative macrophages promote plaque angiogenesis, leakiness, inflammation, and progression via the CD163/HIF1α/VEGF-A pathway.
Hypothalamic ER–associated degradation regulates POMC maturation, feeding, and age-associated obesity J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-19 Geun Hyang Kim; Guojun Shi; Diane R.M. Somlo; Leena Haataja; Soobin Song; Qiaoming Long; Eduardo A. Nillni; Malcolm J. Low; Peter Arvan; Martin G. Myers Jr.; Ling Qi
Pro-opiomelanocortin (POMC) neurons function as key regulators of metabolism and physiology by releasing prohormone-derived neuropeptides with distinct biological activities. However, our understanding of early events in prohormone maturation in the ER remains incomplete. Highlighting the significance of this gap in knowledge, a single POMC cysteine-to-phenylalanine mutation at position 28 (POMC-C28F) is defective for ER processing and causes early onset obesity in a dominant-negative manner in humans through an unclear mechanism. Here, we report a pathologically important role of Sel1L-Hrd1, the protein complex of ER-associated degradation (ERAD), within POMC neurons. Mice with POMC neuron–specific Sel1L deficiency developed age-associated obesity due, at least in part, to the ER retention of POMC that led to hyperphagia. The Sel1L-Hrd1 complex targets a fraction of nascent POMC molecules for ubiquitination and proteasomal degradation, preventing accumulation of misfolded and aggregated POMC, thereby ensuring that another fraction of POMC can undergo normal posttranslational processing and trafficking for secretion. Moreover, we found that the disease-associated POMC-C28F mutant evades ERAD and becomes aggregated due to the presence of a highly reactive unpaired cysteine thiol at position 50. Thus, this study not only identifies ERAD as an important mechanism regulating POMC maturation within the ER, but also provides insights into the pathogenesis of monogenic obesity associated with defective prohormone folding.
Severe peri-ictal respiratory dysfunction is common in Dravet syndrome J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-11 YuJaung Kim; Eduardo Bravo; Caitlin K. Thirnbeck; Lori A. Smith-Mellecker; Se Hee Kim; Brian K. Gehlbach; Linda C. Laux; Xiuqiong Zhou; Douglas R. Nordli Jr.; George B. Richerson
Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. Patients with DS have a high risk of sudden unexplained death in epilepsy (SUDEP), widely believed to be due to cardiac mechanisms. Here we show that patients with DS commonly have peri-ictal respiratory dysfunction. One patient had severe and prolonged postictal hypoventilation during video EEG monitoring and died later of SUDEP. Mice with an Scn1aR1407X/+ loss-of-function mutation were monitored and died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures were induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea, bradycardia, and death were prevented by the same drugs given at doses high enough to cross the blood-brain barrier. When given via intracerebroventricular infusion at a very low dose, a muscarinic receptor antagonist prevented apnea, bradycardia, and death. We conclude that SUDEP in patients with DS can result from primary central apnea, which can cause bradycardia, presumably via a direct effect of hypoxemia on cardiac muscle.
A common variant alters SCN5A–miR-24 interaction and associates with heart failure mortality J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-19 Xiaoming Zhang; Jin-Young Yoon; Michael Morley; Jared M. McLendon; Kranti A. Mapuskar; Rebecca Gutmann; Haider Mehdi; Heather L. Bloom; Samuel C. Dudley; Patrick T. Ellinor; Alaa A. Shalaby; Raul Weiss; W.H. Wilson Tang; Christine S. Moravec; Madhurmeet Singh; Anne L. Taylor; Clyde W. Yancy; Arthur M. Feldman; Dennis M. McNamara; Kaikobad Irani; Douglas R. Spitz; Patrick Breheny; Kenneth B. Margulies; Barry London; Ryan L. Boudreau
SCN5A encodes the voltage-gated Na+ channel NaV1.5 that is responsible for depolarization of the cardiac action potential and rapid intercellular conduction. Mutations disrupting the SCN5A coding sequence cause inherited arrhythmias and cardiomyopathy, and single-nucleotide polymorphisms (SNPs) linked to SCN5A splicing, localization, and function associate with heart failure–related sudden cardiac death. However, the clinical relevance of SNPs that modulate SCN5A expression levels remains understudied. We recently generated a transcriptome-wide map of microRNA (miR) binding sites in human heart, evaluated their overlap with common SNPs, and identified a synonymous SNP (rs1805126) adjacent to a miR-24 site within the SCN5A coding sequence. This SNP was previously shown to reproducibly associate with cardiac electrophysiological parameters, but was not considered to be causal. Here, we show that miR-24 potently suppresses SCN5A expression and that rs1805126 modulates this regulation. We found that the rs1805126 minor allele associates with decreased cardiac SCN5A expression and that heart failure subjects homozygous for the minor allele have decreased ejection fraction and increased mortality, but not increased ventricular tachyarrhythmias. In mice, we identified a potential basis for this in discovering that decreased Scn5a expression leads to accumulation of myocardial reactive oxygen species. Together, these data reiterate the importance of considering the mechanistic significance of synonymous SNPs as they relate to miRs and disease, and highlight a surprising link between SCN5A expression and nonarrhythmic death in heart failure.
TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-19 YouJin Lee; Per Harald Jonson; Jaakko Sarparanta; Johanna Palmio; Mohona Sarkar; Anna Vihola; Anni Evilä; Tiina Suominen; Sini Penttilä; Marco Savarese; Mridul Johari; Marie-Christine Minot; David Hilton-Jones; Paul Maddison; Patrick Chinnery; Jens Reimann; Cornelia Kornblum; Torsten Kraya; Stephan Zierz; Carolyn Sue; Hans Goebel; Asim Azfer; Stuart H. Ralston; Peter Hackman; Robert C. Bucelli; J. Paul Taylor; Conrad C. Weihl; Bjarne Udd
Multisystem proteinopathy (MSP) involves disturbances of stress granule (SG) dynamics and autophagic protein degradation that underlie the pathogenesis of a spectrum of degenerative diseases that affect muscle, brain, and bone. Specifically, identical mutations in the autophagic adaptor SQSTM1 can cause varied penetrance of 4 distinct phenotypes: amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Paget’s disease of the bone, and distal myopathy. It has been hypothesized that clinical pleiotropy relates to additional genetic determinants, but thus far, evidence has been lacking. Here, we provide evidence that a TIA1 (p.N357S) variant dictates a myodegenerative phenotype when inherited, along with a pathogenic SQSTM1 mutation. Experimentally, the TIA1-N357S variant significantly enhances liquid-liquid–phase separation in vitro and impairs SG dynamics in living cells. Depletion of SQSTM1 or the introduction of a mutant version of SQSTM1 similarly impairs SG dynamics. TIA1-N357S–persistent SGs have increased association with SQSTM1, accumulation of ubiquitin conjugates, and additional aggregated proteins. Synergistic expression of the TIA1-N357S variant and a SQSTM1-A390X mutation in myoblasts leads to impaired SG clearance and myotoxicity relative to control myoblasts. These findings demonstrate a pathogenic connection between SG homeostasis and ubiquitin-mediated autophagic degradation that drives the penetrance of an MSP phenotype.
Intracellular lipid metabolism impairs β cell compensation during diet-induced obesity J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-19 Risheng Ye; Ruth Gordillo; Mengle Shao; Toshiharu Onodera; Zhe Chen; Shiuhwei Chen; Xiaoli Lin; Jeffrey A. SoRelle; Xiaohong Li; Miao Tang; Mark P. Keller; Regina Kuliawat; Alan D. Attie; Rana K. Gupta; William L. Holland; Bruce Beutler; Joachim Herz; Philipp E. Scherer
The compensatory proliferation of insulin-producing β cells is critical to maintaining glucose homeostasis at the early stage of type 2 diabetes. Failure of β cells to proliferate results in hyperglycemia and insulin dependence in patients. To understand the effect of the interplay between β cell compensation and lipid metabolism upon obesity and peripheral insulin resistance, we eliminated LDL receptor–related protein 1 (LRP1), a pleiotropic mediator of cholesterol, insulin, energy metabolism, and other cellular processes, in β cells. Upon high-fat diet exposure, LRP1 ablation significantly impaired insulin secretion and proliferation of β cells. The diminished insulin signaling was partly contributed to by the hypersensitivity to glucose-induced, Ca2+-dependent activation of Erk and the mTORC1 effector p85 S6K1. Surprisingly, in LRP1-deficient islets, lipotoxic sphingolipids were mitigated by improved lipid metabolism, mediated at least in part by the master transcriptional regulator PPARγ2. Acute overexpression of PPARγ2 in β cells impaired insulin signaling and insulin secretion. Elimination of Apbb2, a functional regulator of LRP1 cytoplasmic domain, also impaired β cell function in a similar fashion. In summary, our results uncover the double-edged effects of intracellular lipid metabolism on β cell function and viability in obesity and type 2 diabetes and highlight LRP1 as an essential regulator of these processes.
HIV latency is reversed by ACSS2-driven histone crotonylation J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-19 Guochun Jiang; Don Nguyen; Nancie M. Archin; Steven A. Yukl; Gema Méndez-Lagares; Yuyang Tang; Maher M. Elsheikh; George R. Thompson III; Dennis J. Hartigan-O’Connor; David M. Margolis; Joseph K. Wong; Satya Dandekar
Eradication of HIV-1 (HIV) is hindered by stable viral reservoirs. Viral latency is epigenetically regulated. While the effects of histone acetylation and methylation at the HIV long-terminal repeat (LTR) have been described, our knowledge of the proviral epigenetic landscape is incomplete. We report that a previously unrecognized epigenetic modification of the HIV LTR, histone crotonylation, is a regulator of HIV latency. Reactivation of latent HIV was achieved following the induction of histone crotonylation through increased expression of the crotonyl-CoA–producing enzyme acyl-CoA synthetase short-chain family member 2 (ACSS2). This reprogrammed the local chromatin at the HIV LTR through increased histone acetylation and reduced histone methylation. Pharmacologic inhibition or siRNA knockdown of ACSS2 diminished histone crotonylation–induced HIV replication and reactivation. ACSS2 induction was highly synergistic in combination with either a protein kinase C agonist (PEP005) or a histone deacetylase inhibitor (vorinostat) in reactivating latent HIV. In the SIV-infected nonhuman primate model of AIDS, the expression of ACSS2 was significantly induced in intestinal mucosa in vivo, which correlated with altered fatty acid metabolism. Our study links the HIV/SIV infection–induced fatty acid enzyme ACSS2 to HIV latency and identifies histone lysine crotonylation as a novel epigenetic regulator for HIV transcription that can be targeted for HIV eradication.
Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling J. Clin. Invest. (IF 12.784) Pub Date : 2018-03-01 Samir Softic; Manoj K. Gupta; Guo-Xiao Wang; Shiho Fujisaka; Brian T. O’Neill; Tata Nageswara Rao; Jennifer Willoughby; Carole Harbison; Kevin Fitzgerald; Olga Ilkayeva; Christopher B. Newgard; David E. Cohen; C. Ronald Kahn
Original citation: J Clin Invest. 2017;127(11):4059–4074. https://doi.org/10.1172/JCI94585 Citation for this corrigendum: J Clin Invest. 2018;128(3):1199. https://doi.org/10.1172/JCI99009 Following publication of this article, the authors became aware that reference 22 was not accurately described in Results. The corrected paragraph that pertains to this reference appears below. ChREBP has many overlapping functions with SREBP1c, as both have been reported to increase expression of lipogenic genes, such as Fasn and Acaca (20). ChREBP has also been shown to induce fibroblast growth factor 21 (Fgf21), which can regulate fatty acid oxidation (21). In the current study, we observed increased expression of fatty acid oxidation genes in animals fed HFD+Gluc compared with HFD+Fruct in concert with increased expression of total ChREBP (Figures 3D and 4D). However, ChREBP has actually been shown to decrease expression of the key fatty acid oxidation gene CPT1a (22), and our study did not include measures of direct transcriptional activation. Thus, the general increase in fatty acid oxidation genes observed with feeding of HFD+Gluc, including increases in carnitine palmitoyltransferase 2 (Cpt2), family member 12, medium, long, and very long chain acyl–coenzyme A dehydrogenase (Acad12, Acadm, Acadl, Acadvl), acetyl–coenzyme A acyltransferase 2 (Acaa2), and the α and β subunits of hydroxyacyl–coenzyme A dehydrogenase (Hadha and Hadhb), cannot be ascribed to ChREBP. Further studies will be required to fully understand the relevant regulatory networks mediating increased expression of enzymes regulating fatty acid oxidation in mice on HFD+Gluc. However, what is clear is that glucose as compared to fructose supplementation of HFD induces very different programs of metabolic regulation in liver, reflecting both complex transcriptional and posttranscriptional regulation. During the preparation of the manuscript, Figure 2D was inadvertently mislabeled by the journal. The corrected figure part is below. The authors regret the error. Footnotes See the related article at Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling.
CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis J. Clin. Invest. (IF 12.784) Pub Date : 2018-03-01 Yaniv Zohar; Gizi Wildbaum; Rostislav Novak; Andrew L. Salzman; Marcus Thelen; Ronen Alon; Yiftah Barsheshet; Christopher L. Karp; Nathan Karin
Original citation: J Clin Invest. 2014;124(5):2009–2022. https://doi.org/10.1172/JCI71951 Citation for this corrigendum: J Clin Invest. 2018;128(3):1200–1201. https://doi.org/10.1172/JCI120358 The Editors recently posted an Expression of Concern for this article due to duplication of some of the flow cytometry plots in Figures 5C and 7A (1). The authors have completed three replicate experiments for the panels in question, and the updated findings appear below. The revised experiments were conducted by Yaniv Zohar, and the analysis was completed independently in a blinded fashion. The authors report in Figure 5C that repeated administration of CXCL11-Ig increased the in vivo polarization of IL-10hi CD4+ T cells, suggesting that CXCL11 supports Tr1 polarization. In addition, the authors state that Experiments 1 and 2 suggest that the administration of CXCL10-Ig induced IFNhi Th1 cells, consistent with the notion of the differential functions of CXCL10 and CXCL11 in T cell polarization. This finding was not confirmed in Experiment 3. Figure 7A shows reduced accumulation of injected CD4+ T cells in the draining LN and spinal cord, but not the spleen, consistent with the original findings of the article. The authors regret the errors and appreciate the opportunity to correct the article. 1. J Clin Invest. 2017;127(10):3913. https://doi.org/10.1172/JCI97015 Footnotes See the related article at CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis.
Fructose metabolism and metabolic disease J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-01 Sarah A. Hannou; Danielle E. Haslam; Nicola M. McKeown; Mark A. Herman
Increased sugar consumption is increasingly considered to be a contributor to the worldwide epidemics of obesity and diabetes and their associated cardiometabolic risks. As a result of its unique metabolic properties, the fructose component of sugar may be particularly harmful. Diets high in fructose can rapidly produce all of the key features of the metabolic syndrome. Here we review the biology of fructose metabolism as well as potential mechanisms by which excessive fructose consumption may contribute to cardiometabolic disease.
Blood will out: vascular contributions to Alzheimer’s disease J. Clin. Invest. (IF 12.784) Pub Date : 2018-02-01 Sidney Strickland
The fundamental pathology in Alzheimer’s disease (AD) is neuronal dysfunction leading to cognitive impairment. The amyloid-β peptide (Aβ), derived from amyloid precursor protein, is one driver of AD, but how it leads to neuronal dysfunction is not established. In this Review, I discuss the complexity of AD and possible cause-and-effect relationships between Aβ and the vascular and hemostatic systems. AD can be considered a multifactorial syndrome with various contributing pathological mechanisms. Therefore, as is routinely done with cancer, it will be important to classify patients with respect to their disease signature so that specific pathologies, including vascular pathways, can be therapeutically targeted.
Micro(glial)-managing executive function: white matter inflammation drives catatonia J. Clin. Invest. (IF 12.784) Pub Date : 2017-12-18 Sarah E. Pease-Raissi; Jonah R. Chan
White matter abnormalities are prevalent in neuropsychiatric disorders such as schizophrenia, but it is unclear whether these abnormalities represent a cause or consequence of these disorders. Reduced levels of the myelin protein 2′-3′-cyclic nucleotide 3′-phosphodiesterase (CNP) are associated with the schizophrenic symptom catatonia in both humans and mouse models. In this issue of the JCI, Janova et al. show that reduced CNP levels correlate with catatonia and white matter inflammation in human subjects. Furthermore, they demonstrate that microglial ablation prevents and alleviates catatonic signs in Cnp–/– mice, indicating that microglial-mediated inflammation causes catatonia. Together, this study identifies a cellular mechanism by which subtle myelin abnormalities cause low-grade neuroinflammation and catatonic behavior.
A double negative: inhibition of hepatic Gi signaling improves glucose homeostasis J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-16 Allen M. Spiegel
Hepatic glucose production (HGP) is a key determinant of glucose homeostasis. Glucagon binding to its cognate seven-transmembrane Gs-coupled receptor in hepatocytes stimulates cAMP production, resulting in increased HGP. In this issue of the JCI, Rossi and colleagues tested the hypothesis that activation of hepatic Gi–coupled receptors, which should inhibit cAMP production, would oppose the cAMP-inducing action of glucagon and thereby decrease HGP. Surprisingly, however, the opposite occurred: activation of Gi signaling increased HGP via a novel mechanism, while inhibition of Gi signaling reduced HGP. These results define a new physiologic role for hepatic Gi signaling and identify a potential therapeutic target for HGP regulation.
The host protecting the tumor from the host — targeting PD‑L1 expressed by host cells J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-16 David H. Munn
Tumors frequently escape from immune surveillance by hijacking the natural control mechanisms that regulate normal immune responses. The programmed death-1 receptor (PD‑1) on T cells normally helps limit excessive immune activation, but it can also suppress beneficial antitumor immunity. In the clinic, blocking either PD‑1 or one of its principal counterligands, programmed death–ligand 1 (PD‑L1), can lead to dramatic responses in certain patients. Because PD‑L1 can be expressed by both the tumor cells themselves and also the host cells, including host immune cells, the actual mechanistic target of therapy has remained unclear. In the current issue of the JCI, two papers, one by Tang and colleagues and the other by Lin and colleagues, used a variety of mouse tumor models to demonstrate that the relevant target for therapy in each case was the PD‑L1 molecules expressed by host cells and not by tumor cells. If this finding is generalized to humans, then it would suggest that the tumor persuades the host to actively suppress its own attempted immune response against the tumor cells.
Unravelling the fate of functional PD1+ T cells in chronic viral hepatitis J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-08 Eleanor Barnes
Hepatitis B virus (HBV) infection can be managed clinically with nucleos(t)ide therapy, which suppresses viral replication; however, these drugs must often be used long term, as they are unable to fully eliminate the virus. For many patients, discontinuation of treatment results in viral resurgence and hepatic flare, and there is not a reliable way to identify those individuals that can be successfully taken off nucleos(t)ide therapy. In this issue of the JCI, Rivino and colleagues report on their use of a multipronged approach to investigate potential biomarkers indicative of HBV-infected patients who can safely stop nucleos(t)ide therapy. The authors identified a population of HBV-specific, PD1-positive T cells that was present in HBV-infected patients who successfully discontinued treatment without hepatic flare, but not in those that developed flare upon treatment cessation. Together, these results support the concept that PD1+ cells may play an important role in viral control, the further evaluation of this T cell subset in preventing hepatic flare, and the development of assays to better detect this PD1+ T cell population in HBV-infected patients on nucleos(t)ide therapy.
B cells as biomarkers: predicting immune checkpoint therapy adverse events J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-08 Shannon M. Liudahl; Lisa M. Coussens
Immune checkpoint inhibitors are becoming a cornerstone of cancer immunotherapy as a result of their clinical success in relieving immune suppression and driving durable antitumor T cell responses in certain subsets of patients. Unfortunately, checkpoint inhibition is also associated with treatment-related toxicities that result in a myriad of side effects, ranging from mild and manageable to severe and debilitating. In this issue of the JCI, Das and colleagues report an association between early therapy-induced changes in circulating B cells and an increased risk of high-grade immune-related adverse events (IRAEs) in patients treated with checkpoint inhibitors that target cytotoxic T lymphocyte–associated antigen-4 (CTLA4) and programmed cell death protein 1 (PD1). These findings identify potential predictive biomarkers for high-grade IRAEs that may be leveraged to improve patient monitoring and may prompt new treatment strategies to prevent IRAEs.
PD-L1 on host cells is essential for PD-L1 blockade–mediated tumor regression J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-16 Haidong Tang; Yong Liang; Robert A. Anders; Janis M. Taube; Xiangyan Qiu; Aditi Mulgaonkar; Xin Liu; Susan M. Harrington; Jingya Guo; Yangchun Xin; Yahong Xiong; Kien Nham; William Silvers; Guiyang Hao; Xiankai Sun; Mingyi Chen; Raquibul Hannan; Jian Qiao; Haidong Dong; Hua Peng; Yang-Xin Fu
Programmed death–ligand 1 (PD-L1) expression on tumor cells is essential for T cell impairment, and PD-L1 blockade therapy has shown unprecedented durable responses in several clinical studies. Although higher expression of PD-L1 on tumor cells is associated with a better immune response after Ab blockade, some PD-L1–negative patients also respond to this therapy. In the current study, we explored whether PD-L1 on tumor or host cells was essential for anti–PD-L1–mediated therapy in 2 different murine tumor models. Using real-time imaging in whole tumor tissues, we found that anti–PD-L1 Ab accumulates in tumor tissues, regardless of the status of PD-L1 expression on tumor cells. We further observed that, while PD-L1 on tumor cells was largely dispensable for the response to checkpoint blockade, PD-L1 in host myeloid cells was essential for this response. Additionally, PD-L1 signaling in defined antigen-presenting cells (APCs) negatively regulated and inhibited T cell activation. PD-L1 blockade inside tumors was not sufficient to mediate regression, as limiting T cell trafficking reduced the efficacy of the blockade. Together, these findings demonstrate that PD-L1 expressed in APCs, rather than on tumor cells, plays an essential role in checkpoint blockade therapy, providing an insight into the mechanisms of this therapy.
Cancer-associated fibroblasts regulate endothelial adhesion protein LPP to promote ovarian cancer chemoresistance J. Clin. Invest. (IF 12.784) Pub Date : 2017-12-18 Cecilia S. Leung; Tsz-Lun Yeung; Kay-Pong Yip; Kwong-Kwok Wong; Samuel Y. Ho; Lingegowda S. Mangala; Anil K. Sood; Gabriel Lopez-Berestein; Jianting Sheng; Stephen T.C. Wong; Michael J. Birrer; Samuel C. Mok
The molecular mechanism by which cancer-associated fibroblasts (CAFs) confer chemoresistance in ovarian cancer is poorly understood. The purpose of the present study was to evaluate the roles of CAFs in modulating tumor vasculature, chemoresistance, and disease progression. Here, we found that CAFs upregulated the lipoma-preferred partner (LPP) gene in microvascular endothelial cells (MECs) and that LPP expression levels in intratumoral MECs correlated with survival and chemoresistance in patients with ovarian cancer. Mechanistically, LPP increased focal adhesion and stress fiber formation to promote endothelial cell motility and permeability. siRNA-mediated LPP silencing in ovarian tumor–bearing mice improved paclitaxel delivery to cancer cells by decreasing intratumoral microvessel leakiness. Further studies showed that CAFs regulate endothelial LPP via a calcium-dependent signaling pathway involving microfibrillar-associated protein 5 (MFAP5), focal adhesion kinase (FAK), ERK, and LPP. Thus, our findings suggest that targeting endothelial LPP enhances the efficacy of chemotherapy in ovarian cancer. Our data highlight the importance of CAF–endothelial cell crosstalk signaling in cancer chemoresistance and demonstrate the improved efficacy of using LPP-targeting siRNA in combination with cytotoxic drugs.
Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage J. Clin. Invest. (IF 12.784) Pub Date : 2017-12-18 Che-Feng Chang; Brittany A. Goods; Michael H. Askenase; Matthew D. Hammond; Stephen C. Renfroe; Arthur F. Steinschneider; Margaret J. Landreneau; Youxi Ai; Hannah E. Beatty; Luís Henrique Angenendt da Costa; Matthias Mack; Kevin N. Sheth; David M. Greer; Anita Huttner; Daniel Coman; Fahmeed Hyder; Sourav Ghosh; Carla V. Rothlin; J. Christopher Love; Lauren H. Sansing
Macrophages are a source of both proinflammatory and restorative functions in damaged tissue through complex dynamic phenotypic changes. Here, we sought to determine whether monocyte-derived macrophages (MDMs) contribute to recovery after acute sterile brain injury. By profiling the transcriptional dynamics of MDMs in the murine brain after experimental intracerebral hemorrhage (ICH), we found robust phenotypic changes in the infiltrating MDMs over time and demonstrated that MDMs are essential for optimal hematoma clearance and neurological recovery. Next, we identified the mechanism by which the engulfment of erythrocytes with exposed phosphatidylserine directly modulated the phenotype of both murine and human MDMs. In mice, loss of receptor tyrosine kinases AXL and MERTK reduced efferocytosis of eryptotic erythrocytes and hematoma clearance, worsened neurological recovery, exacerbated iron deposition, and decreased alternative activation of macrophages after ICH. Patients with higher circulating soluble AXL had poor 1-year outcomes after ICH onset, suggesting that therapeutically augmenting efferocytosis may improve functional outcomes by both reducing tissue injury and promoting the development of reparative macrophage responses. Thus, our results identify the efferocytosis of eryptotic erythrocytes through AXL/MERTK as a critical mechanism modulating macrophage phenotype and contributing to recovery from ICH.
HIF-1α promotes autophagic proteolysis of Dicer and enhances tumor metastasis J. Clin. Invest. (IF 12.784) Pub Date : 2017-12-18 Hui-Huang Lai; Jie-Ning Li; Ming-Yang Wang; Hsin-Yi Huang; Carlo M. Croce; Hui-Lung Sun; Yu-Jhen Lyu; Jui-Wen Kang; Ching-Feng Chiu; Mien-Chie Hung; Hiroshi I. Suzuki; Pai-Sheng Chen
HIF-1α, one of the most extensively studied oncogenes, is activated by a variety of microenvironmental factors. The resulting biological effects are thought to depend on its transcriptional activity. The RNAse enzyme Dicer is frequently downregulated in human cancers, which has been functionally linked to enhanced metastatic properties; however, current knowledge of the upstream mechanisms regulating Dicer is limited. In the present study, we identified Dicer as a HIF-1α–interacting protein in multiple types of cancer cell lines and different human tumors. HIF-1α downregulated Dicer expression by facilitating its ubiquitination by the E3 ligase Parkin, thereby enhancing autophagy-mediated degradation of Dicer, which further suppressed the maturation of known tumor suppressors, such as the microRNA let-7 and microRNA-200b. Consequently, expression of HIF-1α facilitated epithelial-mesenchymal transition (EMT) and metastasis in tumor-bearing mice. Thus, this study uncovered a connection between oncogenic HIF-1α and the tumor-suppressive Dicer. This function of HIF-1α is transcription independent and occurs through previously unrecognized protein interaction–mediated ubiquitination and autophagic proteolysis.
Dinaciclib induces immunogenic cell death and enhances anti-PD1–mediated tumor suppression J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-16 Dewan Md Sakib Hossain; Sarah Javaid; Mingmei Cai; Chunsheng Zhang; Anandi Sawant; Marlene Hinton; Manjiri Sathe; Jeff Grein; Wendy Blumenschein; Elaine M. Pinheiro; Alissa Chackerian
Blockade of the checkpoint inhibitor programmed death 1 (PD1) has demonstrated remarkable success in the clinic for the treatment of cancer; however, a majority of tumors are resistant to anti-PD1 monotherapy. Numerous ongoing clinical combination therapy studies will likely reveal additional therapeutics that complement anti-PD1 blockade. Recent studies found that immunogenic cell death (ICD) improves T cell responses against different tumors, thus indicating that ICD may further augment antitumor immunity elicited by anti-PD1. Here, we observed antitumor activity following combinatorial therapy with anti-PD1 Ab and the cyclin-dependent kinase inhibitor dinaciclib in immunocompetent mouse tumor models. Dinaciclib induced a type I IFN gene signature within the tumor, leading us to hypothesize that dinaciclib potentiates the effects of anti-PD1 by eliciting ICD. Indeed, tumor cells treated with dinaciclib showed the hallmarks of ICD including surface calreticulin expression and release of high mobility group box 1 (HMGB1) and ATP. Mice treated with both anti-PD1 and dinaciclib showed increased T cell infiltration and DC activation within the tumor, indicating that this combination improves the overall quality of the immune response generated. These findings identify a potential mechanism for the observed benefit of combining dinaciclib and anti-PD1, in which dinaciclib induces ICD, thereby converting the tumor cell into an endogenous vaccine and boosting the effects of anti-PD1.
PBX transcription factors drive pulmonary vascular adaptation to birth J. Clin. Invest. (IF 12.784) Pub Date : 2017-12-18 David J. McCulley; Mark D. Wienhold; Elizabeth A. Hines; Timothy A. Hacker; Allison Rogers; Ryan J. Pewowaruk; Rediet Zewdu; Naomi C. Chesler; Licia Selleri; Xin Sun
A critical event in the adaptation to extrauterine life is relaxation of the pulmonary vasculature at birth, allowing for a rapid increase in pulmonary blood flow that is essential for efficient gas exchange. Failure of this transition leads to pulmonary hypertension (PH), a major cause of newborn mortality associated with preterm birth, infection, hypoxia, and malformations including congenital diaphragmatic hernia (CDH). While individual vasoconstrictor and dilator genes have been identified, the coordination of their expression is not well understood. Here, we found that lung mesenchyme–specific deletion of CDH-implicated genes encoding pre–B cell leukemia transcription factors (Pbx) led to lethal PH in mice shortly after birth. Loss of Pbx genes resulted in the misexpression of both vasoconstrictors and vasodilators in multiple pathways that converge to increase phosphorylation of myosin in vascular smooth muscle (VSM) cells, causing persistent constriction. While targeting endothelin and angiotensin, which are upstream regulators that promote VSM contraction, was not effective, treatment with the Rho-kinase inhibitor Y-27632 reduced vessel constriction and PH in Pbx-mutant mice. These results demonstrate a lung-intrinsic, herniation-independent cause of PH in CDH. More broadly, our findings indicate that neonatal PH can result from perturbation of multiple pathways and suggest that targeting the downstream common effectors may be a more effective treatment for neonatal PH.
Hepatitis B virus–specific T cells associate with viral control upon nucleos(t)ide-analogue therapy discontinuation J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-08 Laura Rivino; Nina Le Bert; Upkar S. Gill; Kamini Kunasegaran; Yang Cheng; Damien Z.M. Tan; Etienne Becht; Navjyot K. Hansi; Graham R. Foster; Tung-Hung Su; Tai-Chung Tseng; Seng Gee Lim; Jia-Horng Kao; Evan W. Newell; Patrick T.F. Kennedy; Antonio Bertoletti
BACKGROUND. The clinical management of chronic hepatitis B virus (HBV) patients is based exclusively on virological parameters that cannot independently determine in which patients nucleos(t)ide-analogue (NUC) therapy can be safely discontinued. NUCs efficiently suppress viral replication, but do not eliminate HBV. Thus, therapy discontinuation can be associated with virological and biochemical relapse and, consequently, therapy in the majority is life-long.
RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-16 Andisheh Abedini; Ping Cao; Annette Plesner; Jinghua Zhang; Meilun He; Julia Derk; Sachi A. Patil; Rosa Rosario; Jacqueline Lonier; Fei Song; Hyunwook Koh; Huilin Li; Daniel P. Raleigh; Ann Marie Schmidt
Islet amyloidosis is characterized by the aberrant accumulation of islet amyloid polypeptide (IAPP) in pancreatic islets, resulting in β cell toxicity, which exacerbates type 2 diabetes and islet transplant failure. It is not fully clear how IAPP induces cellular stress or how IAPP-induced toxicity can be prevented or treated. We recently defined the properties of toxic IAPP species. Here, we have identified a receptor-mediated mechanism of islet amyloidosis–induced proteotoxicity. In human diabetic pancreas and in cellular and mouse models of islet amyloidosis, increased expression of the receptor for advanced glycation endproducts (RAGE) correlated with human IAPP–induced (h-IAPP–induced) β cell and islet inflammation, toxicity, and apoptosis. RAGE selectively bound toxic intermediates, but not nontoxic forms of h-IAPP, including amyloid fibrils. The isolated extracellular ligand–binding domains of soluble RAGE (sRAGE) blocked both h-IAPP toxicity and amyloid formation. Inhibition of the interaction between h-IAPP and RAGE by sRAGE, RAGE-blocking antibodies, or genetic RAGE deletion protected pancreatic islets, β cells, and smooth muscle cells from h-IAPP–induced inflammation and metabolic dysfunction. sRAGE-treated h-IAPP Tg mice were protected from amyloid deposition, loss of β cell area, β cell inflammation, stress, apoptosis, and glucose intolerance. These findings establish RAGE as a mediator of IAPP-induced toxicity and suggest that targeting the IAPP/RAGE axis is a potential strategy to mitigate this source of β cell dysfunction in metabolic disease.
Insulin exits skeletal muscle capillaries by fluid-phase transport J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-08 Ian M. Williams; Francisco A. Valenzuela; Steven D. Kahl; Doraiswami Ramkrishna; Adam R. Mezo; Jamey D. Young; K. Sam Wells; David H. Wasserman
Before insulin can stimulate myocytes to take up glucose, it must first move from the circulation to the interstitial space. The continuous endothelium of skeletal muscle (SkM) capillaries restricts insulin’s access to myocytes. The mechanism by which insulin crosses this continuous endothelium is critical to understand insulin action and insulin resistance; however, methodological obstacles have limited understanding of endothelial insulin transport in vivo. Here, we present an intravital microscopy technique to measure the rate of insulin efflux across the endothelium of SkM capillaries. This method involves development of a fully bioactive, fluorescent insulin probe, a gastrocnemius preparation for intravital microscopy, an automated vascular segmentation algorithm, and the use of mathematical models to estimate endothelial transport parameters. We combined direct visualization of insulin efflux from SkM capillaries with modeling of insulin efflux kinetics to identify fluid-phase transport as the major mode of transendothelial insulin efflux in mice. Model-independent experiments demonstrating that insulin movement is neither saturable nor affected by insulin receptor antagonism supported this result. Our finding that insulin enters the SkM interstitium by fluid-phase transport may have implications in the pathophysiology of SkM insulin resistance as well as in the treatment of diabetes with various insulin analogs.
Early B cell changes predict autoimmunity following combination immune checkpoint blockade J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-08 Rituparna Das; Noffar Bar; Michelle Ferreira; Aaron M. Newman; Lin Zhang; Jithendra Kini Bailur; Antonella Bacchiocchi; Harriet Kluger; Wei Wei; Ruth Halaban; Mario Sznol; Madhav V. Dhodapkar; Kavita M. Dhodapkar
Combination checkpoint blockade (CCB) targeting inhibitory CTLA4 and PD1 receptors holds promise for cancer therapy. Immune-related adverse events (IRAEs) remain a major obstacle for the optimal application of CCB in cancer. Here, we analyzed B cell changes in patients with melanoma following treatment with either anti-CTLA4 or anti-PD1, or in combination. CCB therapy led to changes in circulating B cells that were detectable after the first cycle of therapy and characterized by a decline in circulating B cells and an increase in CD21lo B cells and plasmablasts. PD1 expression was higher in the CD21lo B cells, and B cell receptor sequencing of these cells demonstrated greater clonality and a higher frequency of clones compared with CD21hi cells. CCB induced proliferation in the CD21lo compartment, and single-cell RNA sequencing identified B cell activation in cells with genomic profiles of CD21lo B cells in vivo. Increased clonality of circulating B cells following CCB occurred in some patients. Treatment-induced changes in B cells preceded and correlated with both the frequency and timing of IRAEs. Patients with early B cell changes experienced higher rates of grade 3 or higher IRAEs 6 months after CCB. Thus, early changes in B cells following CCB may identify patients who are at increased risk of IRAEs, and preemptive strategies targeting B cells may reduce toxicities in these patients.
Influenza-specific lung-resident memory T cells are proliferative and polyfunctional and maintain diverse TCR profiles J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-08 Angela Pizzolla; Thi H.O. Nguyen; Sneha Sant; Jade Jaffar; Tom Loudovaris; Stuart I. Mannering; Paul G. Thomas; Glen P. Westall; Katherine Kedzierska; Linda M. Wakim
The human lung harbors a large population of resident memory T cells (Trm cells). These cells are perfectly positioned to mediate rapid protection against respiratory pathogens such as influenza virus, a highly contagious respiratory pathogen that continues to be a major public health burden. Animal models show that influenza-specific lung CD8+ Trm cells are indispensable for crossprotection against pulmonary infection with different influenza virus strains. However, it is not known whether influenza-specific CD8+ Trm cells present within the human lung have the same critical role in modulating the course of the disease. Here, we showed that human lung contains a population of CD8+ Trm cells that are highly proliferative and have polyfunctional progeny. We observed that different influenza virus–specific CD8+ T cell specificities differentiated into Trm cells with varying efficiencies and that the size of the influenza-specific CD8+ T cell population persisting in the lung directly correlated with the efficiency of differentiation into Trm cells. To our knowledge, we provide the first ex vivo dissection of paired T cell receptor (TCR) repertoires of human influenza–specific CD8+ Trm cells. Our data reveal diverse TCR profiles within the human lung Trm cells and a high degree of clonal sharing with other CD8+ T cell populations, a feature important for effective T cell function and protection against the generation of viral-escape mutants.
Microglia ablation alleviates myelin-associated catatonic signs in mice J. Clin. Invest. (IF 12.784) Pub Date : 2017-12-18 Hana Janova; Sahab Arinrad; Evan Balmuth; Marina Mitjans; Johannes Hertel; Mohamad Habes; Robert A. Bittner; Hong Pan; Sandra Goebbels; Martin Begemann; Ulrike C. Gerwig; Sönke Langner; Hauke B. Werner; Sarah Kittel-Schneider; Georg Homuth; Christos Davatzikos; Henry Völzke; Brian L. West; Andreas Reif; Hans Jörgen Grabe; Susann Boretius; Hannelore Ehrenreich; Klaus-Armin Nave
The underlying cellular mechanisms of catatonia, an executive “psychomotor” syndrome that is observed across neuropsychiatric diseases, have remained obscure. In humans and mice, reduced expression of the structural myelin protein CNP is associated with catatonic signs in an age-dependent manner, pointing to the involvement of myelin-producing oligodendrocytes. Here, we showed that the underlying cause of catatonic signs is the low-grade inflammation of white matter tracts, which marks a final common pathway in Cnp-deficient and other mutant mice with minor myelin abnormalities. The inhibitor of CSF1 receptor kinase signaling PLX5622 depleted microglia and alleviated the catatonic symptoms of Cnp mutants. Thus, microglia and low-grade inflammation of myelinated tracts emerged as the trigger of a previously unexplained mental condition. We observed a very high (25%) prevalence of individuals with catatonic signs in a deeply phenotyped schizophrenia sample (n = 1095). Additionally, we found the loss-of-function allele of a myelin-specific gene (CNP rs2070106-AA) associated with catatonia in 2 independent schizophrenia cohorts and also associated with white matter hyperintensities in a general population sample. Since the catatonic syndrome is likely a surrogate marker for other executive function defects, we suggest that microglia-directed therapies may be considered in psychiatric disorders associated with myelin abnormalities.
Hepatic Gi signaling regulates whole-body glucose homeostasis J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-16 Mario Rossi; Lu Zhu; Sara M. McMillin; Sai Prasad Pydi; Shanu Jain; Lei Wang; Yinghong Cui; Regina J. Lee; Amanda H. Cohen; Hideaki Kaneto; Morris J. Birnbaum; Yanling Ma; Yaron Rotman; Jie Liu; Travis J. Cyphert; Toren Finkel; Owen P. McGuinness; Jürgen Wess
An increase in hepatic glucose production (HGP) is a key feature of type 2 diabetes. Excessive signaling through hepatic Gs–linked glucagon receptors critically contributes to pathologically elevated HGP. Here, we tested the hypothesis that this metabolic impairment can be counteracted by enhancing hepatic Gi signaling. Specifically, we used a chemogenetic approach to selectively activate Gi-type G proteins in mouse hepatocytes in vivo. Unexpectedly, activation of hepatic Gi signaling triggered a pronounced increase in HGP and severely impaired glucose homeostasis. Moreover, increased Gi signaling stimulated glucose release in human hepatocytes. A lack of functional Gi-type G proteins in hepatocytes reduced blood glucose levels and protected mice against the metabolic deficits caused by the consumption of a high-fat diet. Additionally, we delineated a signaling cascade that links hepatic Gi signaling to ROS production, JNK activation, and a subsequent increase in HGP. Taken together, our data support the concept that drugs able to block hepatic Gi–coupled GPCRs may prove beneficial as antidiabetic drugs.
Critical roles of αII spectrin in brain development and epileptic encephalopathy J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-16 Yu Wang; Tuo Ji; Andrew D. Nelson; Katarzyna Glanowska; Geoffrey G. Murphy; Paul M. Jenkins; Jack M. Parent
The nonerythrocytic α-spectrin-1 (SPTAN1) gene encodes the cytoskeletal protein αII spectrin. Mutations in SPTAN1 cause early infantile epileptic encephalopathy type 5 (EIEE5); however, the role of αII spectrin in neurodevelopment and EIEE5 pathogenesis is unknown. Prior work suggests that αII spectrin is absent in the axon initial segment (AIS) and contributes to a diffusion barrier in the distal axon. Here, we have shown that αII spectrin is expressed ubiquitously in rodent and human somatodendritic and axonal domains. CRISPR-mediated deletion of Sptan1 in embryonic rat forebrain by in utero electroporation caused altered dendritic and axonal development, loss of the AIS, and decreased inhibitory innervation. Overexpression of human EIEE5 mutant SPTAN1 in embryonic rat forebrain and mouse hippocampal neurons led to similar developmental defects that were also observed in EIEE5 patient-derived neurons. Additionally, patient-derived neurons displayed aggregation of spectrin complexes. Taken together, these findings implicate αII spectrin in critical aspects of dendritic and axonal development and synaptogenesis, and support a dominant-negative mechanism of SPTAN1 mutations in EIEE5.
Role for VGLUT2 in selective vulnerability of midbrain dopamine neurons J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-16 Thomas Steinkellner; Vivien Zell; Zachary J. Farino; Mark S. Sonders; Michael Villeneuve; Robin J. Freyberg; Serge Przedborski; Wei Lu; Zachary Freyberg; Thomas S. Hnasko
Parkinson’s disease is characterized by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). DA neurons in the ventral tegmental area are more resistant to this degeneration than those in the SNc, though the mechanisms for selective resistance or vulnerability remain poorly understood. A key to elucidating these processes may lie within the subset of DA neurons that corelease glutamate and express the vesicular glutamate transporter VGLUT2. Here, we addressed the potential relationship between VGLUT expression and DA neuronal vulnerability by overexpressing VGLUT in DA neurons of flies and mice. In Drosophila, VGLUT overexpression led to loss of select DA neuron populations. Similarly, expression of VGLUT2 specifically in murine SNc DA neurons led to neuronal loss and Parkinsonian behaviors. Other neuronal cell types showed no such sensitivity, suggesting that DA neurons are distinctively vulnerable to VGLUT2 expression. Additionally, most DA neurons expressed VGLUT2 during development, and coexpression of VGLUT2 with DA markers increased following injury in the adult. Finally, conditional deletion of VGLUT2 made DA neurons more susceptible to Parkinsonian neurotoxins. These data suggest that the balance of VGLUT2 expression is a crucial determinant of DA neuron survival. Ultimately, manipulation of this VGLUT2-dependent process may represent an avenue for therapeutic development.
JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-22 Anna Sophia McKenney; Allison N. Lau; Amritha Varshini Hanasoge Somasundara; Barbara Spitzer; Andrew M. Intlekofer; Jihae Ahn; Kaitlyn Shank; Franck T. Rapaport; Minal A. Patel; Efthymia Papalexi; Alan H. Shih; April Chiu; Elizaveta Freinkman; Esra A. Akbay; Mya Steadman; Raj Nagaraja; Katharine Yen; Julie Teruya-Feldstein; Kwok-Kin Wong; Raajit Rampal; Matthew G. Vander Heiden; Craig B. Thompson; Ross L. Levine
Patients with myeloproliferative neoplasms (MPNs) frequently progress to bone marrow failure or acute myeloid leukemia (AML), and mutations in epigenetic regulators such as the metabolic enzyme isocitrate dehydrogenase (IDH) are associated with poor outcomes. Here, we showed that combined expression of Jak2V617F and mutant IDH1R132H or Idh2R140Q induces MPN progression, alters stem/progenitor cell function, and impairs differentiation in mice. Jak2V617F Idh2R140Q–mutant MPNs were sensitive to small-molecule inhibition of IDH. Combined inhibition of JAK2 and IDH2 normalized the stem and progenitor cell compartments in the murine model and reduced disease burden to a greater extent than was seen with JAK inhibition alone. In addition, combined JAK2 and IDH2 inhibitor treatment also reversed aberrant gene expression in MPN stem cells and reversed the metabolite perturbations induced by concurrent JAK2 and IDH2 mutations. Combined JAK2 and IDH2 inhibitor therapy also showed cooperative efficacy in cells from MPN patients with both JAK2mut and IDH2mut mutations. Taken together, these data suggest that combined JAK and IDH inhibition may offer a therapeutic advantage in this high-risk MPN subtype.
Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade–mediated tumor regression J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-16 Heng Lin; Shuang Wei; Elaine M. Hurt; Michael D. Green; Lili Zhao; Linda Vatan; Wojciech Szeliga; Ronald Herbst; Paul W. Harms; Leslie A. Fecher; Pankaj Vats; Arul M. Chinnaiyan; Christopher D. Lao; Theodore S. Lawrence; Max Wicha; Junzo Hamanishi; Masaki Mandai; Ilona Kryczek; Weiping Zou
Programmed death-1 receptor (PD-L1, B7-H1) and programmed cell death protein 1 (PD-1) pathway blockade is a promising therapy for treating cancer. However, the mechanistic contribution of host and tumor PD-L1 and PD-1 signaling to the therapeutic efficacy of PD-L1 and PD-1 blockade remains elusive. Here, we evaluated 3 tumor-bearing mouse models that differ in their sensitivity to PD-L1 blockade and demonstrated a loss of therapeutic efficacy of PD-L1 blockade in immunodeficient mice and in PD-L1– and PD-1–deficient mice. In contrast, neither knockout nor overexpression of PD-L1 in tumor cells had an effect on PD-L1 blockade efficacy. Human and murine studies showed high levels of functional PD-L1 expression in dendritic cells and macrophages in the tumor microenvironments and draining lymph nodes. Additionally, expression of PD-L1 on dendritic cells and macrophages in ovarian cancer and melanoma patients correlated with the efficacy of treatment with either anti–PD-1 alone or in combination with anti–CTLA-4. Thus, PD-L1–expressing dendritic cells and macrophages may mechanistically shape and therapeutically predict clinical efficacy of PD-L1/PD-1 blockade.
OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-16 Alix F. Leblanc; Jason A. Sprowl; Paola Alberti; Alessia Chiorazzi; W. David Arnold; Alice A. Gibson; Kristen W. Hong; Marissa S. Pioso; Mingqing Chen; Kevin M. Huang; Vamsi Chodisetty; Olivia Costa; Tatiana Florea; Peter de Bruijn; Ron H. Mathijssen; Raquel E. Reinbolt; Maryam B. Lustberg; Lara E. Sucheston-Campbell; Guido Cavaletti; Alex Sparreboom; Shuiying Hu
Paclitaxel is among the most widely used anticancer drugs and is known to cause a dose-limiting peripheral neurotoxicity, the initiating mechanisms of which remain unknown. Here, we identified the murine solute carrier organic anion–transporting polypeptide B2 (OATP1B2) as a mediator of paclitaxel-induced neurotoxicity. Additionally, using established tests to assess acute and chronic paclitaxel-induced neurotoxicity, we found that genetic or pharmacologic knockout of OATP1B2 protected mice from mechanically induced allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes. The function of this transport system was inhibited by the tyrosine kinase inhibitor nilotinib through a noncompetitive mechanism, without compromising the anticancer properties of paclitaxel. Collectively, our findings reveal a pathway that explains the fundamental basis of paclitaxel-induced neurotoxicity, with potential implications for its therapeutic management.
Zinc transporter Slc39a8 is essential for cardiac ventricular compaction J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-16 Wen Lin; Deqiang Li; Lan Cheng; Li Li; Feiyan Liu; Nicholas J. Hand; Jonathan A. Epstein; Daniel J. Rader
Isolated left ventricular noncompaction (LVNC) results from excessive trabeculation and impaired myocardial compaction during heart development. The extracellular matrix (ECM) that separates endocardium from myocardium plays a critical but poorly understood role in ventricular trabeculation and compaction. In an attempt to characterize solute carrier family 39 member 8–null (Slc39a8-null) mice, we discovered that homozygous null embryos do not survive embryogenesis and exhibit a cardiac phenotype similar to human LVNC. Slc39a8 encodes a divalent metal cation importer that has been implicated in ECM degradation through the zinc/metal regulatory transcription factor 1 (Zn/MTF1) axis, which promotes the expression of ECM-degrading enzymes, including Adamts metalloproteinases. Here, we have shown that Slc39a8 is expressed by endothelial cells in the developing mouse heart, where it serves to maintain cellular Zn levels. Furthermore, Slc39a8-null hearts exhibited marked ECM accumulation and reduction of several Adamts metalloproteinases. Consistent with the in vivo observations, knockdown of SLC39A8 in HUVECs decreased ADAMTS1 transcription by decreasing cellular Zn uptake and, as a result, MTF1 transcriptional activity. Our study thus identifies a gene underlying ventricular trabeculation and compaction development, and a pathway regulating ECM during myocardial morphogenesis.
Endothelial Tie1–mediated angiogenesis and vascular abnormalization promote tumor progression and metastasis J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-22 Silvia La Porta; Lise Roth; Mahak Singhal; Carolin Mogler; Carleen Spegg; Benjamin Schieb; Xianghu Qu; Ralf H. Adams; H. Scott Baldwin; Soniya Savant; Hellmut G. Augustin
The endothelial tyrosine kinase receptor Tie1 remains poorly characterized, largely owing to its orphan receptor status. Global Tie1 inactivation causes late embryonic lethality, thereby reflecting its importance during development. Tie1 also plays pivotal roles during pathologies such as atherosclerosis and tumorigenesis. In order to study the contribution of Tie1 to tumor progression and metastasis, we conditionally deleted Tie1 in endothelial cells at different stages of tumor growth and metastatic dissemination. Tie1 deletion during primary tumor growth in mice led to a decrease in microvessel density and an increase in mural cell coverage with improved vessel perfusion. Reduced angiogenesis and enhanced vascular normalization resulted in a progressive increase of intratumoral necrosis that caused a growth delay only at later stages of tumor progression. Concomitantly, surgical removal of the primary tumor decreased the number of circulating tumor cells, reduced metastasis, and prolonged overall survival. Additionally, Tie1 deletion in experimental murine metastasis models prevented extravasation of tumor cells into the lungs and reduced metastatic foci. Taken together, the data support Tie1 as a therapeutic target by defining its regulatory functions during angiogenesis and vascular abnormalization and identifying its role during metastasis.
Aberrant TGF-β activation in bone tendon insertion induces enthesopathy-like disease J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-22 Xiao Wang; Liang Xie; Janet Crane; Gehua Zhen; Fengfeng Li; Ping Yang; Manman Gao; Ruoxian Deng; Yiguo Wang; Xiaohua Jia; Cunyi Fan; Mei Wan; Xu Cao
Enthesopathy is a disorder of bone, tendon, or ligament insertion. It represents one-fourth of all tendon-ligament diseases and is one of the most difficult tendon-ligament disorders to treat. Despite its high prevalence, the exact pathogenesis of this condition remains unknown. Here, we show that TGF-β was activated in both a semi-Achilles tendon transection (SMTS) mouse model and in a dorsiflexion immobilization (DI) mouse model of enthesopathy. High concentrations of active TGF-β recruited mesenchymal stromal stem cells (MSCs) and led to excessive vessel formation, bone deterioration, and fibrocartilage calcification. Transgenic expression of active TGF-β1 in bone also induced enthesopathy with a phenotype similar to that observed in SMTS and DI mice. Systemic inhibition of TGF-β activity by injection of 1D11, a TGF-β–neutralizing antibody, but not a vehicle antibody, attenuated the excessive vessel formation and restored uncoupled bone remodeling in SMTS mice. 1D11-treated SMTS fibrocartilage had increased proteoglycan and decreased collagen X and matrix metalloproteinase 13 expression relative to control antibody treatment. Notably, inducible knockout of the TGF-β type II receptor in mouse MSCs preserved the bone microarchitecture and fibrocartilage composition after SMTS relative to the WT littermate controls. Thus, elevated levels of active TGF-β in the enthesis bone marrow induce the initial pathological changes of enthesopathy, indicating that TGF-β inhibition could be a potential therapeutic strategy.
Long noncoding RNA BLACAT2 promotes bladder cancer–associated lymphangiogenesis and lymphatic metastasis J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-22 Wang He; Guangzheng Zhong; Ning Jiang; Bo Wang; Xinxiang Fan; Changhao Chen; Xu Chen; Jian Huang; Tianxin Lin
The prognosis for bladder cancer patients with lymph node (LN) metastasis is dismal and only minimally improved by current treatment modalities. Elucidation of the molecular mechanisms that underlie LN metastasis may provide clinical therapeutic strategies for LN-metastatic bladder cancer. Here, we report that a long noncoding RNA LINC00958, which we have termed bladder cancer–associated transcript 2 (BLACAT2), was markedly upregulated in LN-metastatic bladder cancer and correlated with LN metastasis. Overexpression of BLACAT2 promoted bladder cancer–associated lymphangiogenesis and lymphatic metastasis in both cultured bladder cancer cell lines and mouse models. Furthermore, we demonstrate that BLACAT2 epigenetically upregulated VEGF-C expression by directly associating with WDR5, a core subunit of human H3K4 methyltransferase complexes. Importantly, administration of an anti–VEGF-C antibody inhibited LN metastasis in BLACAT2-overexpressing bladder cancer. Taken together, these findings uncover a molecular mechanism in the lymphatic metastasis of bladder cancer and indicate that BLACAT2 may represent a target for clinical intervention in LN-metastatic bladder cancer.
Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ T cells J. Clin. Invest. (IF 12.784) Pub Date : 2018-01-22 Szu-Han Huang; Yanqin Ren; Allison S. Thomas; Dora Chan; Stefanie Mueller; Adam R. Ward; Shabnum Patel; Catherine M. Bollard; Conrad Russell Cruz; Sara Karandish; Ronald Truong; Amanda B. Macedo; Alberto Bosque; Colin Kovacs; Erika Benko; Alicja Piechocka-Trocha; Hing Wong; Emily Jeng; Douglas F. Nixon; Ya-Chi Ho; Robert F. Siliciano; Bruce D. Walker; R. Brad Jones
The presence of persistent, latent HIV reservoirs in CD4+ T cells obstructs current efforts to cure infection. The so-called kick-and-kill paradigm proposes to purge these reservoirs by combining latency-reversing agents with immune effectors such as cytotoxic T lymphocytes. Support for this approach is largely based on success in latency models, which do not fully reflect the makeup of latent reservoirs in individuals on long-term antiretroviral therapy (ART). Recent studies have shown that CD8+ T cells have the potential to recognize defective proviruses, which comprise the vast majority of all infected cells, and that the proviral landscape can be shaped over time due to in vivo clonal expansion of infected CD4+ T cells. Here, we have shown that treating CD4+ T cells from ART-treated individuals with combinations of potent latency-reversing agents and autologous CD8+ T cells consistently reduced cell-associated HIV DNA, but failed to deplete replication-competent virus. These CD8+ T cells recognized and potently eliminated CD4+ T cells that were newly infected with autologous reservoir virus, ruling out a role for both immune escape and CD8+ T cell dysfunction. Thus, our results suggest that cells harboring replication-competent HIV possess an inherent resistance to CD8+ T cells that may need to be addressed to cure infection.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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