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  • Healthy hosts rule within: ecological forces shaping the gut microbiota
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-05-09
    Mariana X. Byndloss, Sandy R. Pernitzsch, Andreas J. Bäumler

    A balanced gut microbiota is important for human health, but the mechanisms that maintain homeostasis are incompletely understood. Recent insights suggest the host plays a key role in shaping its gut microbiota to be beneficial. While host control in the small intestine curbs bacterial numbers to avoid competition for simple sugars and amino acids, the host limits oxygen availability in the large intestine to obtain microbial fermentation products from fiber. Epithelial cells are major players in imposing ecological control mechanisms, which involves the release of antimicrobial peptides by small-intestinal Paneth cells and maintenance of luminal anaerobiosis by epithelial hypoxia in the colon. Harnessing these epithelial control mechanisms for therapeutic means could provide a novel lynchpin for strategies to remediate dysbiosis.

    更新日期:2018-05-09
  • Human intestinal pro-inflammatory CD11chighCCR2+CX3CR1+ macrophages, but not their tolerogenic CD11c−CCR2−CX3CR1− counterparts, are expanded in inflammatory bowel disease
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-05-09
    D. Bernardo, A. C. Marin, S. Fernández-Tomé, A. Montalban-Arques, A. Carrasco, E. Tristán, L. Ortega-Moreno, I. Mora-Gutiérrez, A. Díaz-Guerra, R. Caminero-Fernández, P. Miranda, F. Casals, M. Caldas, M. Jiménez, S. Casabona, F. De la Morena, M. Esteve, C. Santander, M. Chaparro, J. P. Gisbert

    Although macrophages (Mϕ) maintain intestinal immune homoeostasis, there is not much available information about their subset composition, phenotype and function in the human setting. Human intestinal Mϕ (CD45+HLA-DR+CD14+CD64+) can be divided into subsets based on the expression of CD11c, CCR2 and CX3CR1. Monocyte-like cells can be identified as CD11chighCCR2+CX3CR1+ cells, a phenotype also shared by circulating CD14+ monocytes. On the contrary, their Mϕ-like tissue-resident counterparts display a CD11c−CCR2−CX3CR1− phenotype. CD11chigh monocyte-like cells produced IL-1β, both in resting conditions and after LPS stimulation, while CD11c− Mϕ-like cells produced IL-10. CD11chigh pro-inflammatory monocyte-like cells, but not the others, were increased in the inflamed colon from patients with inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Tolerogenic IL-10-producing CD11c− Mϕ-like cells were generated from monocytes following mucosal conditioning. Finally, the colonic mucosa recruited circulating CD14+ monocytes in a CCR2-dependent manner, being such capacity expanded in IBD. Mϕ subsets represent, therefore, transition stages from newly arrived pro-inflammatory monocyte-like cells (CD11chighCCR2+CX3CR1+) into tolerogenic tissue-resident (CD11c−CCR2−CX3CR1−) Mϕ-like cells as reflected by the mucosal capacity to recruit circulating monocytes and induce CD11c− Mϕ. The process is nevertheless dysregulated in IBD, where there is an increased migration and accumulation of pro-inflammatory CD11chigh monocyte-like cells.

    更新日期:2018-05-09
  • NADPH oxidases and ROS signaling in the gastrointestinal tract
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-05-09
    Gabriella Aviello, Ulla G. Knaus

    Reactive oxygen species (ROS), initially categorized as toxic by-products of aerobic metabolism, have often been called a double-edged sword. ROS are considered indispensable when host defense and redox signaling is concerned and a threat in inflammatory or degenerative diseases. This generalization does not take in account the diversity of oxygen metabolites being generated, their physicochemical characteristics and their production by distinct enzymes in space and time. NOX/DUOX NADPH oxidases are the only enzymes solely dedicated to ROS production and the prime ROS producer for intracellular and intercellular communication due to their widespread expression and intricate regulation. Here we discuss new insights of how NADPH oxidases act via ROS as multifaceted regulators of the intestinal barrier in homeostasis, infectious disease and intestinal inflammation. A closer look at monogenic VEOIBD and commensals as ROS source supports the view of H2O2 as key beneficial messenger in the barrier ecosystem.

    更新日期:2018-05-09
  • Immune quiescence in the oral mucosa is maintained by a uniquely large population of highly activated Foxp3+ regulatory T cells
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-05-09
    Joo-Young Park, Hyunsoo Chung, Devon T. DiPalma, Xuguang Tai, Jung-Hyun Park

    The oral mucosa is a critical barrier tissue that protects the oral cavity against invading pathogens and foreign antigens. Interestingly, inflammation in the oral cavity is rarely observed, indicating that overt immune activation in this site is actively suppressed. Whether Foxp3+ Treg cells are involved in controlling immunity of the oral mucosa, however, is not fully understood. Here, we show that the oral mucosa is highly enriched in Foxp3+ Treg cells, and that oral mucosa Treg cells are phenotypically distinct from those of LN or spleen, as they expressed copious amounts of the tissue-retention molecule CD103 and unusually high-levels of CTLA4. Acute depletion of Foxp3+ Treg cells had catastrophic effects, resulting in marked infiltration of activated effector T cells that were associated with autoimmunity and tissue destruction of the oral mucosa. Moreover, adoptive transfer of naive CD4 T cells revealed that the oral mucosa is highly ineffective in inducing Foxp3+ Treg cells in situ, so that it depends on recruitment and migration of exogenous Treg cells to populate this mucosal site. Collectively, these results demonstrate a previously unappreciated role and a distinct developmental pathway for Foxp3+ Treg cells in the oral mucosa, which are essential to control local tissue immunity.

    更新日期:2018-05-09
  • Modulation of bacterial metabolism by the microenvironment controls MAIT cell stimulation
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-05-09
    Mathias Schmaler, Alessia Colone, Julian Spagnuolo, Michael Zimmermann, Marco Lepore, Artem Kalinichenko, Sumedha Bhatia, Fabien Cottier, Tobias Rutishauser, Norman Pavelka, Adrian Egli, Elisa Azzali, Marco Pieroni, Gabriele Costantino, Petr Hruz, Uwe Sauer, Lucia Mori, Gennaro De Libero

    Mucosal-associated invariant T (MAIT) cells are abundant innate-like T lymphocytes in mucosal tissues and recognize a variety of riboflavin-related metabolites produced by the microbial flora. Relevant issues are whether MAIT cells are heterogeneous in the colon, and whether the local environment influences microbial metabolism thereby shaping MAIT cell phenotypes and responses. We found discrete MAIT cell populations in human colon, characterized by the diverse expression of transcription factors, cytokines and surface markers, indicative of activated and precisely controlled lymphocyte populations. Similar phenotypes were rare among circulating MAIT cells and appeared when circulating MAIT cells were stimulated with the synthetic antigens 5-(2-oxoethylideneamino)-6-d-ribitylaminouracil, and 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil. Furthermore, bacteria grown in colon-resembling conditions with low oxygen tension and harvested at stationary growth phase, potently activated human MAIT cells. The increased activation correlated with accumulation of the above antigenic metabolites as indicated by mass spectrometry. Thus, the colon environment contributes to mucosal immunity by directly affecting bacterial metabolism, and indirectly controlling the stimulation and differentiation of MAIT cells.

    更新日期:2018-05-09
  • The increased protection and pathology in Mycobacterium tuberculosis-infected IL-27R-alpha-deficient mice is supported by IL-17A and is associated with the IL-17A-induced expansion of multifunctional T cells
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-05-04
    Hanna Erdmann, Jochen Behrends, Kristina Ritter, Alexandra Hölscher, Johanna Volz, Ida Rosenkrands, Christoph Hölscher

    During Mycobacterium tuberculosis (Mtb) infection, mice lacking the IL-27R exhibit lower bacterial burdens but develop an immunopathological sequelae in comparison to wild-type mice. We here show that this phenotype correlates with an enhanced recruitment of antigen-specific CCR6+ CD4+ T cells and an increased frequency of IL-17A-producing CD4+ T cells. By comparing the outcome of Mtb infection in C57BL/6, IL-27R-deficient and IL-27R/IL-17A-double deficient mice, we observed that both the increased protection and elevated immunopathology are supported by IL-17A. Whereas IL-17A neither impacts the development of Tr1 cells nor the expression of PD1 and KLRG1 on T cells in IL-27R-deficient mice during infection, it regulates the presence of multifunctional T-cells in the lungs, co-expressing IFN-γ, IL-2 and TNF. Eventually, IL-17A supports Cxcl9, Cxcl10 and Cxcl13 expression and the granulomatous response in the lungs of infected IL-27R-deficient mice. Taken together, IL-17A contributes to protection in Mtb-infected IL-27R-deficient mice probably through a chemokine-mediated recruitment and strategic positioning of multifunctional T cells in granulomas. As IL-27 limits optimal antimycobacterial protection by inhibiting IL-17A production, blocking of IL-27R-mediated signaling may represent a strategy for improving vaccination and host-directed therapy in tuberculosis. However, because IL-27 also prevents IL-17A-mediated immunopathology, such intervention has to be tightly controlled.

    更新日期:2018-05-04
  • Interleukin-22-deficiency and microbiota contribute to the exacerbation of Toxoplasma gondii-induced intestinal inflammation
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-05-04
    A Couturier-Maillard, N Froux, J Piotet-Morin, C Michaudel, L Brault, J Le Bérichel, A Sénéchal, P Robinet, P Chenuet, S Jejou, L Dumoutier, J C Renauld, J Iovanna, S Huber, VFJ Quesniaux, H Sokol, B Ryffel

    Upon oral infection with Toxoplasma gondii cysts (76 K strain) tachyzoites are released into the intestinal lumen and cross the epithelial barrier causing damage and acute intestinal inflammation in C57BL/6 (B6) mice. Here we investigated the role of microbiota and IL-22 in T.gondii-induced small intestinal inflammation. Oral T.gondii infection in B6 mice causes inflammation with IFNγ and IL-22 production. In IL-22-deficient mice, T.gondii infection augments the Th1 driven inflammation. Deficiency in either IL-22bp, the soluble IL-22 receptor or Reg3γ, an IL-22-dependent antimicrobial lectin/peptide, did not reduce inflammation. Under germ-free conditions, T.gondii-induced inflammation was reduced in correlation with parasite load. But intestinal inflammation is still present in germ-free mice, at low level, in the lamina propria, independently of IL-22 expression. Exacerbated intestinal inflammation driven by absence of IL-22 appears to be independent of IL-22 deficiency associated-dysbiosis as similar inflammation was observed after fecal transplantation of IL-22-/- or WT microbiota to germ-free-WT mice. Our results suggest cooperation between parasite and intestinal microbiota in small intestine inflammation development and endogenous IL-22 seems to exert a protective role independently of its effect on the microbiota. In conclusion, IL-22 participates in T.gondii induced acute small intestinal inflammation independently of microbiota and Reg3γ.

    更新日期:2018-05-04
  • A model of TH17-associated ileal hyperplasia that requires both IL-17A and IFNγ to generate self-tolerance and prevent colitis
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-05-04
    Jonathan C. Jeschke, Christopher G. Mayne, Jennifer Ziegelbauer, Christopher L. DeCiantis, Selina Singh, Suresh N. Kumar, Mariko Suchi, Yoichiro Iwakura, William R. Drobyski, Nita H Salzman, Calvin B. Williams

    Homeostasis in the ileum, which is commonly disrupted in patients with Crohn’s disease, involves ongoing immune responses. To study how homeostatic processes of the ileum impact CD4+T cell responses, we used TCR transgenic tools to breed mice that spontaneously produced CD4+T cells reactive to an antigen expressed in the ileum. At an early age, the ilea of these mice exhibit crypt hyperplasia and accumulate increased numbers of TH17 cells bearing non-transgenic clonotypes. Half of these mice subsequently developed colitis linked to broad mucosal infiltration by TH17 and TH1 cells expressing non-transgenic clonotypes, chronic wasting disease and loss of ileal crypt hyperplasia. By contrast, adult mice with normal growth continued to exhibit TH17-associated ileal crypt hyperplasia and additionally accumulated ileal-reactive Treg cells. Both IL-17A and IFNγ were protective, as their deficiency precluded ileal-reactive Treg accumulation and exacerbated colitic disease. IL-23R blockade prevented progression to colitis, whereas nTreg cell transfers prevented colitic disease, ileal crypt hyperplasia and ileal-reactive Treg accumulation. Thus, our studies identify an IL-17A and IFNγ-dependent homeostatic process that mobilizes ileal-reactive Treg cells and is disrupted by IL-23.

    更新日期:2018-05-04
  • Charles D. Surh, PhD: 1961–2017
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-04-27
    Hilde Cheroutre

    Charles D. Surh, PhD: 1961–2017 Charles D. Surh, PhD: 1961–2017, Published online: 27 April 2018; doi:10.1038/mi.2017.115 Charles D. Surh, PhD: 1961–2017

    更新日期:2018-04-27
  • Pulmonary Regnase-1 orchestrates the interplay of epithelium and adaptive immune systems to protect against pneumonia
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-04-25
    Yoshinari Nakatsuka, Alexis Vandenbon, Takashi Mino, Masanori Yoshinaga, Takuya Uehata, Xiaotong Cui, Ayuko Sato, Tohru Tsujimura, Yutaka Suzuki, Atsuyasu Sato, Tomohiro Handa, Kazuo Chin, Teiji Sawa, Toyohiro Hirai, Osamu Takeuchi

    Inhaled pathogens including Pseudomonas aeruginosa initially encounter airway epithelial cells (AECs), which are poised to evoke cell-intrinsic innate defense, affecting second tier of hematopoietic cell-mediated immune reaction. However, it is largely unknown how pulmonary immune responses mediated by a variety of immune cells are coordinated. Here we show that Regnase-1, an endoribonuclease expressed in AECs and immune cells, plays an essential role in coordinating innate responses and adaptive immunity against P. aeruginosa infection. Intratracheal treatment of mice with heat-killed P. aeruginosa resulted in prolonged disappearance of Regnase-1 consistent with sustained expression of Regnase-1 target inflammatory genes, whereas the transcription factor NF-κB was only transiently activated. AEC-specific deletion of Regnase-1 not only augmented innate defenses against P. aeruginosa but also enhanced secretion of Pseudomonas-specific IgA and Th17 accumulation in the lung, culminating in conferring significant resistance against P. aeruginosa re-infection in vivo. Although Regnase-1 directly controls distinct sets of genes in each of AECs and T cells, degradation of Regnase-1 in both cell types is beneficial for maximizing acquired immune responses. Collectively, these results demonstrate that Regnase-1 orchestrates AEC-mediated and immune cell-mediated host defense against pulmonary bacterial infection.

    更新日期:2018-04-25
  • A screen of Crohn’s disease-associated microbial metabolites identifies ascorbate as a novel metabolic inhibitor of activated human T cells
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-04-25
    Yu-Ling Chang, Maura Rossetti, Hera Vlamakis, David Casero, Gemalene Sunga, Nicholas Harre, Shelley Miller, Romney Humphries, Thaddeus Stappenbeck, Kenneth W. Simpson, R. Balfour Sartor, Gary Wu, James Lewis, Frederic Bushman, Dermot P. B. McGovern, Nita Salzman, James Borneman, Ramnik Xavier, Curtis Huttenhower, Jonathan Braun

    Microbial metabolites are an emerging class of mediators influencing CD4+ T-cell function. To advance the understanding of direct causal microbial factors contributing to Crohn’s disease, we screened 139 predicted Crohn’s disease-associated microbial metabolites for their bioactivity on human CD4+ T-cell functions induced by disease-associated T helper 17 (Th17) polarizing conditions. We observed 15 metabolites with CD4+ T-cell bioactivity, 3 previously reported, and 12 unprecedented. A deeper investigation of the microbe-derived metabolite, ascorbate, revealed its selective inhibition on activated human CD4+ effector T cells, including IL-17A-, IL-4-, and IFNγ-producing cells. Mechanistic assessment suggested the apoptosis of activated human CD4+ T cells associated with selective inhibition of energy metabolism. These findings suggest a substantial rate of relevant T-cell bioactivity among Crohn’s disease-associated microbial metabolites, and evidence for novel modes of bioactivity, including targeting of T-cell energy metabolism.

    更新日期:2018-04-25
  • Human intraepithelial lymphocytes
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-04-20
    Toufic Mayassi, Bana Jabri

    The location of intraepithelial lymphocytes (IEL) between epithelial cells, their effector memory, cytolytic and inflammatory phenotype positions them to kill infected epithelial cells and protect the intestine against pathogens. Human TCRαβ+CD8αβ+ IEL have the dual capacity to recognize modified self via natural killer (NK) receptors (autoreactivity) as well as foreign antigen via the T cell receptor (TCR), which is accomplished in mouse by two cell subsets, the naturally occurring TCRαβ+CD8αα+ and adaptively induced TCRαβ+CD8αβ+ IEL subsets, respectively. The private/oligoclonal nature of the TCR repertoire of both human and mouse IEL suggests local environmental factors dictate the specificity of IEL responses. The line between sensing of foreign antigens and autoreactivity is blurred for IEL in celiac disease, where recognition of stress ligands by induced activating NK receptors in conjunction with inflammatory signals such as IL-15 can result in low-affinity TCR/non-cognate antigen and NK receptor/stress ligand interactions triggering destruction of intestinal epithelial cells.

    更新日期:2018-04-20
  • Aryl hydrocarbon receptor and intestinal immunity
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-04-07
    Bruno Lamas, Jane M. Natividad, Harry Sokol

    Aryl hydrocarbon receptor (AhR) is a member of the basic helix–loop–helix–(bHLH) superfamily of transcription factors, which are associated with cellular responses to environmental stimuli, such as xenobiotics and oxygen levels. Unlike other members of bHLH, AhR is the only bHLH transcription factor that is known to be ligand activated. Early AhR studies focused on understanding the role of AhR in mediating the toxicity and carcinogenesis properties of the prototypic ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In recent years, however, it has become apparent that, in addition to its toxicological involvement, AhR is highly receptive to a wide array of endogenous and exogenous ligands, and that its activation leads to a myriad of key host physiological functions. In this study, we review the current understanding of the functions of AhR in the mucosal immune system with a focus on its role in intestinal barrier function and intestinal immune cells, as well as in intestinal homeostasis.

    更新日期:2018-04-07
  • IL-1β as mucosal vaccine adjuvant: the specific induction of tissue-resident memory T cells improves the heterosubtypic immunity against influenza A viruses
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-03-15
    D. Lapuente, M. Storcksdieck genannt Bonsmann, A. Maaske, V. Stab, V. Heinecke, K. Watzstedt, R. Heß, A. M. Westendorf, W. Bayer, C. Ehrhardt, M. Tenbusch

    A universal influenza vaccine must provide protection against antigenically divergent influenza viruses either through broadly neutralizing antibodies or cross-reactive T cells. Here, intranasal immunizations with recombinant adenoviral vectors (rAd) encoding hemagglutinin (HA) and nucleoprotein (NP) in combination with rAd-Interleukin-(IL)-1β or rAd-IL-18 were evaluated for their efficacy in BALB/c mice. Mucosal delivery of rAd-IL-1β enhanced HA-specific antibody responses including strain-specific neutralizing antibodies. Nevertheless, the beneficial effects on the local T cell responses were much more impressive reflected by increased numbers of CD103+CD69+ tissue-resident memory T cells (TRM). This increased immunogenicity translated into superior protection against infections with homologous and heterologous strains including H1N1, pH1N1, H3N2, and H7N7. Inhibition of the egress of circulating T cells out of the lymph nodes during the heterologous infection had no impact on the degree of protection underscoring the unique potential of TRM for the local containment of mucosal infections. The local co-expression of IL-1β and antigen lead to the activation of critical checkpoints in the formation of TRM including activation of epithelial cells, expression of chemokines and adhesion molecules, recruitment of lung-derived CD103+ DCs, and finally local TRM imprinting. Given the importance of TRM-mediated protection at mucosal barriers, this study has major implications for vaccine development.

    更新日期:2018-03-16
  • Increased intracellular Cl− concentration promotes ongoing inflammation in airway epithelium
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-03-15
    Yi-Lin Zhang, Peng-Xiao Chen, Wei-Jie Guan, Hong-Mei Guo, Zhuo-Er Qiu, Jia-Wen Xu, Yu-Li Luo, Chong-Feng Lan, Jian-Bang Xu, Yuan Hao, Ya-Xia Tan, Ke-Nan Ye, Zhao-Rong Lun, Lei Zhao, Yun-Xin Zhu, Jiehong Huang, Wing-Hung Ko, Wei-De Zhong, Wen-Liang Zhou, Nan-Shan Zhong

    Airway epithelial cells harbor the capacity of active Cl− transepithelial transport and play critical roles in modulating innate immunity. However, whether intracellular Cl− accumulation contributes to relentless airway inflammation remains largely unclear. This study showed that, in airway epithelial cells, intracellular Cl− concentration ([Cl−]i) was increased after Pseudomonas aeruginosa lipopolysaccharide (LPS) stimulation via nuclear factor-κB (NF-κB)–phosphodiesterase 4D (PDE4D)–cAMP signaling pathways. Clamping [Cl−]i at high levels or prolonged treatment with LPS augmented serum- and glucocorticoid-inducible protein kinase 1 (SGK1) phosphorylation and subsequently triggered NF-κB activation in airway epithelial cells, whereas inhibition of SGK1 abrogated airway inflammation in vitro and in vivo. Furthermore, Cl−–SGK1 signaling pathway was pronouncedly activated in patients with bronchiectasis, a chronic airway inflammatory disease. Conversely, hydrogen sulfide (H2S), a sulfhydryl-containing gasotransmitter, confers anti-inflammatory effects through decreasing [Cl−]i via activation of cystic fibrosis transmembrane conductance regulator (CFTR). Our study confirms that intracellular Cl− is a crucial mediator of sustained airway inflammation. Medications that abrogate excessively increased intracellular Cl− may offer novel targets for the management of airway inflammatory diseases.

    更新日期:2018-03-16
  • Intestinal epithelial Caspase-8 signaling is essential to prevent necroptosis during Salmonella Typhimurium induced enteritis
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-03-08
    Manuela Hefele, Iris Stolzer, Barbara Ruder, Gui-Wei He, Mousumi Mahapatro, Stefan Wirtz, Markus F. Neurath, Claudia Günther

    Although induction of host cell death is a pivotal step during bacteria-induced gastroenteritis, the molecular regulation remains to be fully characterized. To expand our knowledge, we investigated the role of the central cell death regulator Caspase-8 in response to Salmonella Typhimurium. Here, we uncovered that intestinal salmonellosis was associated with strong upregulation of members of the host cell death machinery in intestinal epithelial cells (IECs) as an early event, suggesting that elimination of infected IECs represents a host defense strategy. Indeed, Casp8∆IEC mice displayed severe tissue damage and high lethality after infection. Additional deletion of Ripk3 or Mlkl rescued epithelial cell death and lethality of Casp8∆IEC mice, demonstrating the crucial role of Caspase-8 as a negative regulator of necroptosis. While Casp8∆IECTnfr1−/− mice showed improved survival after infection, tissue destruction was similar to Casp8∆IEC mice, indicating that necroptosis partially depends on TNF-α signaling. Although there was no impairment in antimicrobial peptide secretion during the early phase of infection, functional Caspase-8 seems to be required to control pathogen colonization. Collectively, these results demonstrate that Caspase-8 is essential to prevent Salmonella Typhimurium induced enteritis and to ensure host survival by two different mechanisms: maintenance of intestinal barrier function and restriction of pathogen colonization.

    更新日期:2018-03-09
  • Activation of Notch-1 in oral epithelial cells by P. gingivalis triggers the expression of the antimicrobial protein PLA2-IIA
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-03-07
    Ahmad Al-Attar, Yelena Alimova, Sreenatha Kirakodu, Anastasia Kozal, Michael John Novak, Arnold J. Stromberg, Luis Orraca, Janis Gonzalez-Martinez, Melween Martinez, Jeffrey L. Ebersole, Octavio A. Gonzalez

    P. gingivalis (Pg) is an oral pathogen with the ability to induce oral dysbiosis and periodontal disease. Nevertheless, the mechanisms by which mucosal responses to the oral microbiota in the presence of specific pathogens such as Pg could abrogate the host-microbe symbiotic relationship leading to periodontitis remain unclear. Herein, we identified the Notch-1/PLA2-IIA axis as a new molecular pathway through which Pg could be specifically modulating oral epithelial antimicrobial and inflammatory responses. Pg activated Notch-1, and inhibition or silencing of Notch-1 completely abrogated Pg-induced PLA2-IIA in oral epithelial cells (OECs). Activation of Notch-1 and PLA2-IIA production were associated with Pg-produced gingipains. Other oral Gram-positive and Gram-negative species failed to induce similar responses. Pg enhanced OEC antimicrobial activity through PLA2-IIA. Increased Notch-1 activation correlated with higher PLA2-IIA gingival expression and changes in the abundance of specific oral bacteria phyla during periodontal disease. Oral bacterial species exhibited differential antimicrobial susceptibility to PLA2-IIA. These findings support previous evidence suggesting an important role for epithelial Notch-1 activation and PLA2-IIA production during health and disease at mucosal surfaces, and provide new mechanistic information concerning the regulation of epithelial antimicrobial and pro-inflammatory responses modulated by oral pathogenic bacteria associated with periodontal disease.

    更新日期:2018-03-08
  • Notch signaling represents an important checkpoint between follicular T-helper and canonical T-helper 2 cell fate
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-21
    Mark Dell’Aringa, R. Lee Reinhardt

    Type-2 immunity is regulated by two distinct CD4+ T-cell subsets. T follicular helper (Tfh) cells are required for humoral hallmarks of type-2 inflammation. T-helper type-2 (Th2) cells orchestrate type-2 inflammation in peripheral tissues, such as the lung and intestine. Given the importance of Notch signaling in the establishment of other CD4+ T-helper cell subsets, we investigated whether canonical Notch activation could differentially impact Tfh and Th2 cell fate during the induction of type-2 immunity. These studies show that Tfh cell, but not Th2 cell, generation and function is reliant on Notch signaling. While early Tfh cell specification is influenced by functional Notch ligands on classical dendritic cells, functional Notch ligands on cells other than dendritic cells, T cells, B cells, and follicular dendritic cells are sufficient to achieve full Tfh cell commitment. These findings identify Notch signaling as an early lineage-determining factor between Tfh and Th2 cell fate.

    更新日期:2018-02-22
  • Oral cholera vaccination promotes homing of IgA+ memory B cells to the large intestine and the respiratory tract
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-21
    M van Splunter, E van Hoffen, E G Floris-Vollenbroek, H Timmerman, E Lucas-van de Bos, B Meijer, L H Ulfman, B Witteman, J M Wells, S Brugman, H F J Savelkoul, R J J van Neerven

    Oral cholera vaccination is used to induce immune responses in the intestines to protect against cholera infection. However, oral vaccination may also affect immune responses in other mucosal tissues. To study this, tissue-specific homing potential and kinetics of B-cell responses were characterized after oral cholera vaccination. Healthy adult volunteers received two doses of Dukoral® and blood, saliva, nasal wash, and fecal samples were collected over time to detect vaccine-specific antibodies. Additionally, homing potential of lymphocytes to small intestine, colon, airways, skin, and periphery was measured by expression of Integrin β1 and β7, CCR9, CCR10, CCR7, and CLA. After vaccination, antibody responses to cholera toxin B (CTB) and Dukoral® were detected in serum and nasal wash. CTB-specific memory B cells in peripheral blood and tissue homing profiles of memory B cells peaked at day 18. IgA+ memory B cells expressed markers that enable homing to the airways and colon, while IgA− memory B cells primarily expressed small-intestine-homing markers. These data show that oral cholera vaccination has a differential effect on immune responses in various mucosal sites, including the respiratory tract.

    更新日期:2018-02-22
  • Vaccine-induced antigen-specific regulatory T cells attenuate the antiviral immunity against acute influenza virus infection
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-21
    Pin-Hung Lin, Weng-In Wong, Yi-Lan Wang, Meng-Ping Hsieh, Chia-wen Lu, Chieh-Yu Liang, Sung-Hsiang Jui, Fang-Yi Wu, Pei-Jer Chen, Hung-Chih Yang

    Peptide-based T cell vaccines targeting the conserved epitopes of influenza virus can provide cross-protection against distantly related strains, but they are generally not immunogenic. Foreign antigen-specific regulatory T (Treg) cells are induced under subimmunogenic conditions peripherally, although their development and role in vaccine-mediated antiviral immunity is unclear. Here, we demonstrated primary vaccination with peptides alone significantly induced antigen-specific Foxp3+ Treg cells, which were further expanded by repeated vaccination with unadjuvanted peptides. Certain adjuvants, including CpG, suppressed the induction and expansion of antigen-specific Treg cells by peptide vaccination. Interestingly, secondary influenza virus infection significantly increased the frequency of preexisting antigen-specific Treg cells, although primary infection barely induced them. Importantly, specific depletion of vaccine-induced antigen-specific Treg cells promoted influenza viral clearance, indicating their inhibitory role in vivo. Immunization with CpG-adjuvanted peptides by the subcutaneous prime–intranasal-boost strategy restricted the recruitment and accumulation of antigen-specific Treg cells in lung, and stimulated robust T cell immunity. Finally, subcutaneous prime–intranasal-boost immunization with CpG-adjuvanted peptides or whole-inactivated influenza vaccines protected mice from heterosubtypic influenza virus infection. In conclusion, antigen-specific Treg cells induced by peptide vaccines attenuate the antiviral immunity against influenza virus infection. CpG-adjuvanted peptide vaccines provide heterosubtypic influenza protection probably by inhibiting Treg development and enhancing T cell immunity.

    更新日期:2018-02-22
  • B cells are the predominant mediators of early systemic viral dissemination during rectal LCMV infection
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-19
    Martin Trapecar, Shahzada Khan, Benjamin L. Cohn, Frank Wu, Shomyseh Sanjabi

    Determining the magnitude of local immune response during mucosal exposure to viral pathogens is critical to understanding the mechanism of viral pathogenesis. We previously showed that vaginal inoculation of lymphocytic choriomeningitis virus (LCMV) fails to induce a robust innate immune response in the lower female reproductive tract (FRT), allowing high titer viral replication and a delay in T-cell-mediated viral control. Despite this immunological delay, LCMV replication remained confined mainly to the FRT and the draining iliac lymph node. Here, we show that rectal infection with LCMV triggers type I/III interferon responses, followed by innate immune activation and lymphocyte recruitment to the colon. In contrast to vaginal exposure, innate immunity controls LCMV replication in the colon, but virus rapidly disseminates systemically. Virus-induced inflammation promotes the recruitment of LCMV target cells to the colon followed by splenic viral dissemination by infected B cells, and to a lesser extent by CD8 T cells. These findings demonstrate major immunological differences between vaginal and rectal exposure to the same viral pathogen, highlighting unique risks associated with each of these common routes of sexual viral transmission.

    更新日期:2018-02-19
  • The impact of a helminth-modified microbiome on host immunity
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-16
    Tara P. Brosschot, Lisa A. Reynolds

    Intestinal helminths have well-characterized modulatory effects on mammalian immune pathways. Ongoing helminth infection has been associated with both the suppression of allergies and an altered susceptibility to microbial infections. Enteric helminths share a niche with the intestinal microbiota, and the presence of helminths alters the microbiota composition and the metabolic signature of the host. Recent studies have demonstrated that the helminth-modified intestinal microbiome has the capacity to modify host immune responses even in the absence of live helminth infection. This article discusses the mechanisms by which helminths modify the intestinal microbiome of mammals, and reviews the evidence for a helminth-modified microbiome directly influencing host immunity during infectious and inflammatory diseases. Understanding the multifaceted mechanisms that underpin helminth immunomodulation will pave the way for novel therapies to combat infectious and inflammatory diseases.

    更新日期:2018-02-17
  • Pulmonary antigen encounter regulates the establishment of tissue-resident CD8 memory T cells in the lung airways and parenchyma
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-16
    Sean R. McMaster, Alexander N. Wein, Paul R. Dunbar, Sarah L. Hayward, Emily K. Cartwright, Timothy L. Denning, Jacob E. Kohlmeier

    Resident memory CD8 T (TRM) cells in the lung parenchyma (LP) and airways provide heterologous protection against influenza virus challenge. However, scant knowledge exists regarding factors necessary to establish and maintain lung CD8 TRM. Here we demonstrate that, in contrast to mechanisms described for other tissues, airway, and LP CD8 TRM establishment requires cognate antigen recognition in the lung. Systemic effector CD8 T cells could be transiently pulled into the lung in response to localized inflammation, however these effector cells failed to establish tissue residency unless antigen was present in the pulmonary environment. The interaction of effector CD8 T cells with cognate antigen in the lung resulted in increased and prolonged expression of the tissue-retention markers CD69 and CD103, and increased expression of the adhesion molecule VLA-1. The inability of localized inflammation alone to establish lung TRM resulted in decreased viral clearance and increased mortality following heterosubtypic influenza challenge, despite equal numbers of circulating memory CD8 T cells. These findings demonstrate that pulmonary antigen encounter is required for the establishment of lung CD8 TRM and may inform future vaccine strategies to generate robust cellular immunity against respiratory pathogens.

    更新日期:2018-02-17
  • Goblet cell associated antigen passages are inhibited during Salmonella typhimur/cium infection to prevent pathogen dissemination and limit responses to dietary antigens
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-14
    Devesha H. Kulkarni, Keely G. McDonald, Kathryn A. Knoop, Jenny K. Gustafsson, Konrad M. Kozlowski, David A. Hunstad, Mark J. Miller, Rodney D. Newberry

    Dietary antigen acquisition by lamina propria (LP) dendritic cells (DCs) is crucial to induce oral tolerance and maintain homeostasis. However, encountering innocuous antigens during infection can lead to inflammatory responses, suggesting processes may limit steady-state luminal antigen capture during infection. We observed that goblet cell (GC) associated antigen passages (GAPs), a steady-state pathway delivering luminal antigens to LP-DCs, are inhibited during Salmonella infection. GAP inhibition was mediated by IL-1β. Infection abrogated luminal antigen delivery and antigen-specific T cell proliferation in the mesenteric lymph node (MLN). Antigen-specific T cell proliferation to dietary antigen was restored by overriding GAP suppression; however, this did not restore regulatory T cell induction, but induced inflammatory T cell responses. Salmonella translocation to the MLN required GCs and correlated with GAPs. Genetic manipulations overriding GAP suppression, or antibiotics inducing colonic GAPs, but not antibiotics that do not, increased dissemination and worsened outcomes independent of luminal pathogen burden. Thus, steady-state sampling pathways are suppressed during infection to prevent responses to dietary antigens, limit pathogen entry, and lessen the disease. Moreover, antibiotics may worsen Salmonella infection by means beyond blunting gut microbiota colonization resistance, providing new insight into how precedent antibiotic use aggravates enteric infection.

    更新日期:2018-02-14
  • Alteration in nerves and neurotransmitter stimulation of lacrimal gland secretion in the TSP-1−/− mouse model of aqueous deficiency dry eye
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-14
    Sumit Bhattacharya, Laura García-Posadas, Robin R. Hodges, Helen P. Makarenkova, Sharmila Masli, Darlene A. Dartt

    The purpose of this study is to determine neural, vascular, protein secretion, and cellular signaling changes with disease progression in lacrimal glands of the thrombospondin-1−/− (TSP-1−/−) mouse model of dry eye compared to C57BL/6 wild-type (WT) mice. Neural innervation was reduced in TSP-1−/− lacrimal glands compared to WT controls, whereas the number of blood vessels was increased. Intracellular Ca2+ stores and the amount of lysosomes, mitochondria, and secretory granules, but not the endoplasmic reticulum, were reduced in TSP-1−/− compared to WT acini at 12 weeks of age. Ex vivo high KCl-evoked secretion was decreased in TSP-1−/− compared to WT lacrimal gland tissue pieces. The α1D-adrenergic agonist-stimulated response was increased in TSP-1−/− at 4 and 24 weeks but decreased at 12 weeks, and the ATP and MeSATP-stimulated peak [Ca2+]i responses were decreased at 24 weeks. These changes were observed prior to the appearance of mononuclear infiltrates. We conclude that in the lacrimal gland the absence of TSP-1: injures peripheral nerves; blocks efferent nerve activation; decreases protein secretion; and alters intracellular Ca2+ stores. Through these effects the absence of TSP-1 leads to disruption of ocular surface homeostasis and development of dry eye.

    更新日期:2018-02-14
  • GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-07
    Ye Zhao, Feidi Chen, Wei Wu, Mingming Sun, Anthony J Bilotta, Suxia Yao, Yi Xiao, Xiangsheng Huang, Tonyia D Eaves-Pyles, George Golovko, Yuriy Fofanov, Warren D'Souza, Qihong Zhao, Zhanju Liu, Yingzi Cong

    The antimicrobial peptides (AMP) produced by intestinal epithelial cells (IEC) play crucial roles in the regulation of intestinal homeostasis by controlling microbiota. Gut microbiota has been shown to promote IEC expression of RegIIIγ and certain defensins. However, the mechanisms involved are still not completely understood. In this report, we found that IEC expression levels of RegIIIγ and β-defensins 1, 3, and 4 were lower in G protein-coupled receptor (GPR)43−/− mice compared to that of wild-type (WT) mice. Oral feeding with short-chain fatty acids (SCFA) promoted IEC production of RegIIIγ and defensins in mice. Furthermore, SCFA induced RegIIIγ and β-defensins in intestinal epithelial enteroids generated from WT but not GPR43−/− mice. Mechanistically, SCFA activated mTOR and STAT3 in IEC, and knockdown of mTOR and STAT3 impaired SCFA induction of AMP production. Our studies thus demonstrated that microbiota metabolites SCFA promoted IEC RegIIIγ and β-defensins in a GPR43-dependent manner. The data thereby provide a novel pathway by which microbiota regulates IEC expression of AMP and intestinal homeostasis.

    更新日期:2018-02-07
  • Lymphoid tissue-resident Alcaligenes LPS induces IgA production without excessive inflammatory responses via weak TLR4 agonist activity
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-07
    Naoko Shibata, Jun Kunisawa, Koji Hosomi, Yukari Fujimoto, Keisuke Mizote, Naohiro Kitayama, Atsushi Shimoyama, Hitomi Mimuro, Shintaro Sato, Natsuko Kishishita, Ken J Ishii, Koichi Fukase, Hiroshi Kiyono

    Alcaligenes are opportunistic commensal bacteria that reside in gut-associated lymphoid tissues such as Peyer’s patches (PPs); however, how they create and maintain their homeostatic environment, without inducing an excessive inflammatory response remained unclear. We show here that Alcaligenes-derived lipopolysaccharide (Alcaligenes LPS) acts as a weak agonist of toll-like receptor 4 and promotes IL-6 production from dendritic cells, which consequently enhances IgA production. The inflammatory activity of Alcaligenes LPS was weaker than that of Escherichia coli-derived LPS and therefore no excessive inflammation was induced by Alcaligenes LPS in vitro or in vivo. Alcaligenes LPS also showed adjuvanticity, inducing antigen-specific immune responses without excessive inflammation. These findings reveal the presence of commensal bacteria-mediated homeostatic inflammatory conditions within PPs that produce optimal IgA induction without causing pathogenic inflammation and suggest that Alcaligenes LPS could be a safe and potent adjuvant.

    更新日期:2018-02-07
  • Respiratory syncytial virus activates epidermal growth factor receptor to suppress interferon regulatory factor 1-dependent interferon-lambda and antiviral defense in airway epithelium
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-07
    A Kalinowski, B T Galen, I F Ueki, Y Sun, A Mulenos, A Osafo-Addo, B Clark, J Joerns, W Liu, J A Nadel, C S Dela Cruz, J L Koff

    Respiratory syncytial virus (RSV) persists as a significant human pathogen that continues to contribute to morbidity and mortality. In children, RSV is the leading cause of lower respiratory tract infections, and in adults RSV causes pneumonia and contributes to exacerbations of chronic lung diseases. RSV induces airway epithelial inflammation by activation of the epidermal growth factor receptor (EGFR), a tyrosine kinase receptor. Recently, EGFR inhibition was shown to decrease RSV infection, but the mechanism(s) for this effect are not known. Interferon (IFN) signaling is critical for innate antiviral responses, and recent experiments have implicated IFN-λ (lambda), a type III IFN, as the most significant IFN for mucosal antiviral immune responses to RSV infection. However, a role for RSV-induced EGFR activation to suppress airway epithelial antiviral immunity has not been explored. Here, we show that RSV-induced EGFR activation suppresses IFN regulatory factor (IRF) 1-induced IFN-λ production and increased viral infection, and we implicate RSV F protein to mediate this effect. EGFR inhibition, during viral infection, augmented IRF1, IFN-λ, and decreased RSV titers. These results suggest a mechanism for EGFR inhibition to suppress RSV by activation of endogenous epithelial antiviral defenses, which may be a potential target for novel therapeutics.

    更新日期:2018-02-07
  • Molecular and cellular signatures underlying superior immunity against Bordetella pertussis upon pulmonary vaccination
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-07
    R H M Raeven, J Brummelman, J L A Pennings, L van der Maas, K Helm, W Tilstra, A van der Ark, A Sloots, P van der Ley, W van Eden, W Jiskoot, E van Riet, C A C M van Els, G F A Kersten, W G H Han, B Metz

    Molecular and cellular signatures underlying superior immunity against Bordetella pertussis upon pulmonary vaccination Molecular and cellular signatures underlying superior immunity against Bordetella pertussis upon pulmonary vaccination, Published online: 07 February 2018; doi:10.1038/mi.2017.110 Molecular and cellular signatures underlying superior immunity against Bordetella pertussis upon pulmonary vaccination

    更新日期:2018-02-07
  • Leptin receptor q223r polymorphism influences neutrophil mobilization after Clostridium difficile infection
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-01-24
    S Jose, M M Abhyankar, A Mukherjee, J Xue, H Andersen, D B Haslam, R Madan

    Clostridium difficile is the leading cause of nosocomial infections in the United States. Clinical disease outcomes after C. difficile infection (CDI) are dependent on intensity of host inflammatory responses. Specifically, peak peripheral white blood cell (WBC) count >20 × 109 l−1 is an indicator of adverse outcomes in CDI patients, and is associated with higher 30-day mortality. We show that homozygosity for a common single nucleotide polymorphism (Q to R mutation in leptin receptor that is present in up to 50% of people), significantly increases the risk of having peak peripheral WBC count >20 × 109 l−1 (odds ratio=5.41; P=0.0023) in CDI patients. In a murine model of CDI, we demonstrate that mice homozygous for the same single nucleotide polymorphism (RR mice) have more blood and tissue leukocytes (specifically neutrophils), exaggerated tissue inflammation, and higher mortality as compared with control mice, despite similar pathogen burden. Further, we show that neutrophilia in RR mice is mediated by gut microbiota-directed expression of CXC chemokine receptor 2 (CXCR2), which promotes the release of neutrophils from bone marrow reservoir. Overall these studies provide novel mechanistic insights into the role of human genetic polymorphisms and gut microbiota in regulating the fundamental biological process of CDI-induced neutrophilia.

    更新日期:2018-01-24
  • Intestinal epithelial Toll-like receptor 4 prevents metabolic syndrome by regulating interactions between microbes and intestinal epithelial cells in mice
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-01-24
    P Lu, C P Sodhi, Y Yamaguchi, H Jia, T Prindle Jr., W B Fulton, A Vikram, K J Bibby, M J Morowitz, D J Hackam

    Little is known about the pathogenesis of metabolic syndrome, although Toll-like receptor 4 (TLR4) has been implicated. We investigated whether TLR4 in the intestinal epithelium regulates metabolic syndrome by coordinating interactions between the luminal microbiota and host genes that regulate metabolism. Mice lacking TLR4 in the intestinal epithelium (TLR4ΔIEC), but not mice lacking TLR4 in myeloid cells nor mice lacking TLR4 globally, developed metabolic syndrome; these features were not observed in TLR4ΔIEC mice given antibiotics. Metagenomic analysis of the fecal microbiota revealed differences between TLR4ΔIEC and wild-type mice, while meta-transcriptome analysis of the microbiota showed that intestinal TLR4 affected the expression of microbial genes involved in the metabolism of lipids, amino acids, and nucleotides. Genes regulated by peroxisome proliferator-activated receptors (PPARs) and the antimicrobial peptide lysozyme were significantly downregulated in TLR4ΔIEC mice, suggesting a mechanism by which intestinal TLR4 could exert its effects on the microbiota and metabolic syndrome. Supportingly, antibiotics prevented both downregulation of PPAR genes and the development of metabolic syndrome, while PPAR agonists prevented development of metabolic syndrome in TLR4ΔIEC mice. Thus, intestinal epithelial TLR4 regulates metabolic syndrome through altered host-bacterial signaling, suggesting that microbial or PPAR-based strategies might have therapeutic potential for this disease.

    更新日期:2018-01-24
  • IFN-γ-dependent epigenetic regulation instructs colitogenic monocyte/macrophage lineage differentiation in vivo
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-01-24
    Y Nakanishi, T Sato, K Takahashi, T Ohteki

    Colonic macrophages induce pathogenic inflammation against commensal bacteria, leading to inflammatory bowel disease (IBD). Although the ontogeny of colonic macrophages has been well studied in the past decade, how macrophages gain colitogenic properties during the development of colitis is unknown. Using a chemically induced colitis model, we showed that accumulated Ly6C+ cells consisting of inflammatory monocytes and inflammatory macrophages strongly expressed representative colitogenic mediators such as tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS). The interferon-γ–signal transducer and activator of transcription 1 (IFN-γ–Stat1) pathway was required for generating colitogenic macrophages, given that Stat1−/− mice had less severe colitis and fewer colitogenic macrophages. Notably, IFN-γ induced histone acetylation at the promoter regions of the Tnf and Nos2 loci in the monocyte and macrophage lineage, indicating that IFN-γ-dependent epigenetic regulation instructs the development of the colitogenic monocyte and macrophage lineage in vivo. Collectively, our results provide the essential mechanism by which dysregulated colitogenic monocytes/macrophages develop at the colon mucosa during inflammation, and suggest a new drug target for treating IBD.

    更新日期:2018-01-24
  • Noxa/HSP27 complex delays degradation of ubiquitylated IkBα in airway epithelial cells to reduce pulmonary inflammation
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-01-24
    C Zhang, J T Jones, H S Chand, M G Wathelet, C M Evans, B Dickey, J Xiang, Y A Mebratu, Y Tesfaigzi

    IFN-γ is known as a pro-inflammatory cytokine, but can also block inflammation in certain chronic diseases although the underlying mechanisms are poorly understood. We found that IFN-γ rapidly induced Noxa expression and that extent of inflammation by repeated house dust mite exposure was enhanced in noxa−/− compared with noxa+/+ mice. Noxa expression blocked transforming necrosis factor alpha (TNF-α)-induced nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the production of pro-inflammatory cytokines. Noxa did not affect TNF-α-induced IκBα phosphorylation but the degradation of 48-chain-ubiquitylated IκBα. The Cys25 of Noxa was cross-linked with Cys137 of phospho-HSP27 and both proteins were required for blocking the degradation of ubiquitylated IκBα. Because phospho-HSP27 is present in airway epithelial cells and not in fibroblasts or thymocytes, we generated transgenic mice that inducibly expressed Noxa in airway epithelia. These mice showed protection from allergen-induced inflammation and mucous cell metaplasia by blocking nuclear translocation of NF-κB. Further, we identified a Noxa-derived peptide that prolonged degradation of 48-chain-ubiquitylated IκBα, blocked nuclear translocation of NF-κB, and reduced allergen-induced inflammation in mice. These results suggest that the anti-inflammatory role of the Noxa protein may be restricted to airway epithelial cells and the use of Noxa for therapy of chronic lung diseases may be associated with reduced side effects.

    更新日期:2018-01-24
  • Histamine drives severity of innate inflammation via histamine 4 receptor in murine experimental colitis
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-01-24
    J B Wechsler, A Szabo, C L Hsu, R A Krier-Burris, H A Schroeder, M Y Wang, R G Carter, T E Velez, L M Aguiniga, J B Brown, M L Miller, B K Wershil, T A Barrett, P J Bryce

    Ulcerative colitis (UC) patients exhibit elevated histamine, but how histamine exacerbates disease is unclear as targeting histamine 1 receptor (H1R) or H2R is clinically ineffective. We hypothesized that histamine functioned instead through the other colon-expressed histamine receptor, H4R. In humans, UC patient biopsies exhibited increased H4R RNA and protein expression over control tissue, and immunohistochemistry showed that H4R was in proximity to immunopathogenic myeloperoxidase-positive neutrophils. To characterize this association further, we employed both the oxazolone (Ox)- and dextran sulfate sodium (DSS)-induced experimental colitis mouse models and also found upregulated H4R expression. Mast cell (MC)-derived histamine and H4R drove experimental colitis, as H4R–/– mice had lower symptom scores, neutrophil-recruitment mediators (colonic interleukin-6 (IL-6), CXCL1, CXCL2), and mucosal neutrophil infiltration than wild-type (WT) mice, as did MC-deficient KitW-sh/W-sh mice reconstituted with histidine decarboxylase–deficient (HDC−/−) bone marrow–derived MCs compared with WT-reconstituted mice; adaptive responses remained intact. Furthermore, Rag2−/− × H4R−/− mice had reduced survival, exacerbated colitis, and increased bacterial translocation than Rag2−/− mice, revealing an innate protective antibacterial role for H4R. Taken together, colonic MC-derived histamine initiates granulocyte infiltration into the colonic mucosa through H4R, suggesting alternative therapeutic targets beyond adaptive immunity for UC.

    更新日期:2018-01-24
  • Differential regulation of the transcriptomic and secretomic landscape of sensor and effector functions of human airway epithelial cells
    Mucosal Immunol. (IF 7.478) Pub Date : 
    Roland Lehmann, Mario M Müller, Tilman E Klassert, Dominik Driesch, Magdalena Stock, Anina Heinrich, Theresia Conrad, Christoph Moore, Uta K Schier, Reinhard Guthke, Hortense Slevogt

    Differential regulation of the transcriptomic and secretomic landscape of sensor and effector functions of human airway epithelial cells Differential regulation of the transcriptomic and secretomic landscape of sensor and effector functions of human airway epithelial cells, Published online: 03 January 2018; doi:10.1038/mi.2017.100 Differential regulation of the transcriptomic and secretomic landscape of sensor and effector functions of human airway epithelial cells

    更新日期:2018-01-03
  • Epithelial Hes1 maintains gut homeostasis by preventing microbial dysbiosis
    Mucosal Immunol. (IF 7.478) Pub Date : 
    X-K Guo, J Ou, S Liang, X Zhou, X Hu

    Epithelial Hes1 maintains gut homeostasis by preventing microbial dysbiosis Epithelial Hes1 maintains gut homeostasis by preventing microbial dysbiosis, Published online: 03 January 2018; doi:10.1038/mi.2017.111 Epithelial Hes1 maintains gut homeostasis by preventing microbial dysbiosis

    更新日期:2018-01-03
  • T-bet-independent Th1 response induces intestinal immunopathology during Toxoplasma gondii infection
    Mucosal Immunol. (IF 7.478) Pub Date : 
    Américo H López-Yglesias, Elise Burger, Alessandra Araujo, Andrew T Martin, Felix Yarovinsky

    T-bet-independent Th1 response induces intestinal immunopathology during Toxoplasma gondii infection T-bet-independent Th1 response induces intestinal immunopathology during Toxoplasma gondii infection, Published online: 03 January 2018; doi:10.1038/mi.2017.102 T-bet-independent Th1 response induces intestinal immunopathology during Toxoplasma gondii infection

    更新日期:2018-01-03
  • Immunity to gastrointestinal nematode infections
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-01-03
    D Sorobetea, M Svensson-Frej, R Grencis

    Immunity to gastrointestinal nematode infections Immunity to gastrointestinal nematode infections, Published online: 03 January 2018; doi:10.1038/mi.2017.113 Immunity to gastrointestinal nematode infections

    更新日期:2018-01-03
  • Oral-gut connection: one step closer to an integrated view of the gastrointestinal tract?
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-01-03
    R Lira-Junior, E A Boström

    Although an enrichment of orally derived bacteria is reported in the gut microbiota of patients with several diseases, it is mostly unknown whether oral bacteria can colonize and induce intestinal inflammation. In a recent paper in Science, Atarashi et al.1 from Kenya Honda’s laboratory show that a subset of orally derived bacteria colonizes and persists in the gut, leading to activation of the intestinal immune system and subsequent chronic inflammation in a susceptible host. The impact of oral health status as a potential contributor to inflammatory diseases at distal sites of the body deserves consideration.

    更新日期:2018-01-03
  • Epithelial–mesenchymal transition in Crohn’s disease
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-12-20
    H Jiang, J Shen, Z Ran

    Crohn’s disease (CD) is often accompanied by the complications of intestinal strictures and fistulas. These complications remain obstacles in CD treatment. In recent years, the importance of epithelial–mesenchymal transition in the pathogenesis of CD-associated fistulas and intestinal fibrosis has become apparent. Epithelial–mesenchymal transition refers to a dynamic change, wherein epithelial cells lose their polarity and adherence and acquire migratory function and fibroblast features. During formation of CD-associated fistulas, intestinal epithelial cells dislocate from the basement membrane and migrate to the lining of the fistula tracts, where they convert into transitional cells as a compensatory response under the insufficient wound healing condition. In CD-associated intestinal fibrosis, epithelial–mesenchymal transition may serve as a source of new fibroblasts and consequently lead to overproduction of extracellular matrix. In this review, we present current knowledge of epithelial–mesenchymal transition and its role in the pathogenesis of CD in order to highlight new therapy targets for the associated complications.

    更新日期:2017-12-20
  • Development of immune and microbial environments is independently regulated in the mammary gland
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-12-20
    K Niimi, K Usami, Y Fujita, M Abe, M Furukawa, Y Suyama, Y Sakai, M Kamioka, N Shibata, E J Park, S Sato, H Kiyono, H Yoneyama, H Kitazawa, K Watanabe, T Nochi, H Aso

    Breastfeeding is important for mammals, providing immunological and microbiological advantages to neonates, together with the nutritional supply from the mother. However, the mechanisms of this functional diversity in the mammary gland remain poorly characterized. Here, we show that, similar to the gastrointestinal tract, the mammary gland develops immune and microbial environments consisting of immunoglobulin A (IgA) and the microflora, respectively, both of which are important for protecting neonates and the mother from infectious diseases. The IgA production and microflora development are coordinated in the gastrointestinal tract but seem to be independently regulated in the mammary gland. In particular, the chemokine (C–C motif) ligand 28 and poly-Ig receptor, crucial molecules for the IgA production in milk, were expressed normally in germ-free lactating mice but were almost undetectable in postweaning mothers, regardless of the microflora presence. Our findings offer insights into potentially improving the quality of breastfeeding, using both immunological and microbiological approaches.

    更新日期:2017-12-20
  • Protein kinase C-delta (PKCδ), a marker of inflammation and tuberculosis disease progression in humans, is important for optimal macrophage killing effector functions and survival in mice
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-12-20
    S P Parihar, M Ozturk, M J Marakalala, D T Loots, R Hurdayal, D Beukes, M Van Reenen, D E Zak, S K Mbandi, F Darboe, A Penn-Nicholson, W A Hanekom, M Leitges, T J Scriba, R Guler, F Brombacher

    Protein kinase C-delta (PKCδ), a marker of inflammation and tuberculosis disease progression in humans, is important for optimal macrophage killing effector functions and survival in mice Protein kinase C-delta (PKCδ), a marker of inflammation and tuberculosis disease progression in humans, is important for optimal macrophage killing effector functions and survival in mice, Published online: 20 December 2017; doi:10.1038/mi.2017.108 Protein kinase C-delta (PKCδ), a marker of inflammation and tuberculosis disease progression in humans, is important for optimal macrophage killing effector functions and survival in mice

    更新日期:2017-12-20
  • Early treatment of SIV+ macaques with an α4β7 mAb alters virus distribution and preserves CD4+ T cells in later stages of infection
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-12-20
    P J Santangelo, C Cicala, S N Byrareddy, K T Ortiz, D Little, K E Lindsay, S Gumber, J J Hong, K Jelicic, K A Rogers, C Zurla, F Villinger, A A Ansari, A S Fauci, J Arthos

    Integrin α4β7 mediates the trafficking of leukocytes, including CD4+ T cells, to lymphoid tissues in the gut. Virus mediated damage to the gut is implicated in HIV and SIV mediated chronic immune activation and leads to irreversible damage to the immune system. We employed an immuno-PET/CT imaging technique to evaluate the impact of an anti-integrin α4β7 mAb alone or in combination with ART, on the distribution of both SIV infected cells and CD4+ cells in rhesus macaques infected with SIV. We determined that α4β7 mAb reduced viral antigen in an array of tissues of the lung, spleen, axillary, and inguinal lymph nodes. These sites are not directly linked to α4β7 mediated homing; however, the most pronounced reduction in viral load was observed in the colon. Despite this reduction, α4β7 mAb treatment did not prevent an apparent depletion of CD4+ T cells in gut in the acute phase of infection that is characteristic of HIV/SIV infection. However, α4β7 mAb appeared to facilitate the preservation or restoration of CD4+ T cells in gut tissues at later stages of infection. Since damage to the gut is believed to play a central role in HIV pathogenesis, these results support further evaluation of α4β7 antagonists in the study and treatment of HIV disease.

    更新日期:2017-12-20
  • The cytosolic sensor STING is required for intestinal homeostasis and control of inflammation
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-12-20
    M C C Canesso, L Lemos, T C Neves, F M Marim, T B R Castro, ÉS Veloso, C P Queiroz, J Ahn, H C Santiago, F S Martins, J Alves-Silva, E Ferreira, D C Cara, A T Vieira, G N Barber, S C Oliveira, A M C Faria

    STING (stimulator of interferon genes) is a cytosolic sensor for cyclic dinucleotides and also an adaptor molecule for intracellular DNA receptors. Although STING has important functions in the host defense against pathogens and in autoimmune diseases, its physiological relevance in intestinal homeostasis is largely unknown. In this study, we show that STING−/− mice presented defective protective mechanisms of intestinal mucosa, including decreased number of goblet cells, diminished mucus production, and lower levels of secretory IgA, when compared with wild-type (WT) mice. Fecal content and microbiota DNA could activate STING, indicating a role of this molecule in gut. Microbiota composition was altered in STING−/− mice toward a more inflammatory profile, evidencing a reduction in the Allobacolum and Bifidobacterium groups along with increase in Disulfovibrio bacteria. Absence of STING lead to decrease in induced intraepithelial lymphocytes (IEL) and to increase in group 1 innate lymphoid cell (ILC1) as well as ILC3 frequencies and decrease in ILC2 in the colon. Development and function of Foxp3+ and LAP+ regulatory T cells were also compromised in STING−/− mice. Moreover, these mice were highly susceptible to dextran sodium sulfate–induced colitis, T-cell-induced colitis, and enteric Salmonella typhimurium infection when compared with WT animals. Therefore, our results identify an important role of STING in maintaining gut homeostasis and also a protective effect in controlling gut inflammation.

    更新日期:2017-12-20
  • Macrophages regulate lung ILC2 activation via Pla2g5-dependent mechanisms
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-12-20
    M Yamaguchi, S K Samuchiwal, O Quehenberger, J A Boyce, B Balestrieri

    Group V phospholipase A2 (Pla2g5) is a lipid-generating enzyme necessary for macrophage effector functions in pulmonary inflammation. However, the lipid mediators involved and their cellular targets have not been identified. Mice lacking Pla2g5 showed markedly reduced lung ILC2 activation and eosinophilia following repetitive Alternaria Alternata inhalation. While Pla2g5-null mice had Wt levels of immediate IL-33 release after one Alternaria dose, they failed to upregulate IL-33 in macrophages following repeated Alternaria administration. Unexpectedly, while adoptive transfer of bone marrow-derived (BM)-macrophages restored ILC2 activation and eosinophilia in Alternaria-exposed Pla2g5-null mice, exogenous IL-33 did not. Conversely, transfers of Pla2g5-null BM-macrophages reduced inflammation in Alternaria-exposed Wt mice. Mass spectrometry analysis of free fatty acids (FFAs) demonstrated significantly reduced FFAs (including linoleic acid (LA) and oleic acid (OA)) in lung and BM-macrophages lacking Pla2g5. Exogenous administration of LA or LA+OA to Wt mice sharply potentiated IL-33-induced lung eosinophilia and ILC2 expansion in vitro and in vivo. In contrast, OA potentiated IL-33-induced inflammation and ILC2 expansion in Pla2g5-null mice, but LA was inactive both in vivo and in vitro. Notably, Pla2g5-null ILC2s showed significantly reduced expression of the FFA-receptor-1 compared to Wt ILC2s. Thus, macrophage-associated Pla2g5 contributes significantly to type-2 immunity through regulation of IL-33 induction and FFA-driven ILC2 activation.

    更新日期:2017-12-20
  • Restricted access or access all areas? a new cadherin-like protein upregulated in the inflamed esophagus
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-12-20
    D A Knight, P M Hansbro

    Restricted access or access all areas? a new cadherin-like protein upregulated in the inflamed esophagus Restricted access or access all areas? a new cadherin-like protein upregulated in the inflamed esophagus, Published online: 20 December 2017; doi:10.1038/mi.2017.56 Restricted access or access all areas? a new cadherin-like protein upregulated in the inflamed esophagus

    更新日期:2017-12-20
  • CD103+CD11b+ mucosal classical dendritic cells initiate long-term switched antibody responses to flagellin
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-12-20
    A Flores-Langarica, K Müller Luda, E K Persson, C N Cook, S Bobat, J L Marshall, M W Dahlgren, K Hägerbrand, K M Toellner, M D Goodall, D R Withers, I R Henderson, B Johansson Lindbom, A F Cunningham, W W Agace

    Antibody responses induced at mucosal and nonmucosal sites demonstrate a significant level of autonomy. Here, we demonstrate a key role for mucosal interferon regulatory factor-4 (IRF4)-dependent CD103+CD11b+ (DP), classical dendritic cells (cDCs) in the induction of T-dependent immunoglobulin G (IgG) and immunoglobulin A (IgA) responses in the mesenteric lymph node (MLN) following systemic immunization with soluble flagellin (sFliC). In contrast, IRF8-dependent CD103+CD11b− (SP) are not required for these responses. The lack of this response correlated with a complete absence of sFliC-specific plasma cells in the MLN, small intestinal lamina propria, and surprisingly also the bone marrow (BM). Many sFliC-specific plasma cells accumulating in the BM of immunized wild-type mice expressed α4β7+, suggesting a mucosal origin. Collectively, these results suggest that mucosal DP cDC contribute to the generation of the sFliC-specific plasma cell pool in the BM and thus serve as a bridge linking the mucosal and systemic immune system.

    更新日期:2017-12-20
  • iNOS- and NOX1-dependent ROS production maintains bacterial homeostasis in the ileum of mice
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-12-06
    C Matziouridou, S D C Rocha, O A Haabeth, K Rudi, H Carlsen, A Kielland

    iNOS- and NOX1-dependent ROS production maintains bacterial homeostasis in the ileum of mice iNOS- and NOX1-dependent ROS production maintains bacterial homeostasis in the ileum of mice, Published online: 06 December 2017; doi:10.1038/mi.2017.106 iNOS- and NOX1-dependent ROS production maintains bacterial homeostasis in the ileum of mice

    更新日期:2017-12-15
  • Absence of specific alternatively spliced exon of CD44 in macrophages prevents colitis
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-11-29
    B M Wittig, R Sabat, P Holzlöhner, E Witte-Händel, K Heilmann, K Witte, J Triebus, A Tzankov, J D Laman, B Bokemeyer, L Terracciano, C Schwärzler, H Kohler, R Volkmer, C Loddenkemper, K Wolk, U Hoffmann, U Günthert

    Absence of specific alternatively spliced exon of CD44 in macrophages prevents colitis Absence of specific alternatively spliced exon of CD44 in macrophages prevents colitis, Published online: 29 November 2017; doi:10.1038/mi.2017.98 Absence of specific alternatively spliced exon of CD44 in macrophages prevents colitis

    更新日期:2017-12-15
  • IL-15 supports the generation of protective lung-resident memory CD4 T cells
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-11-29
    T M Strutt, K Dhume, C M Finn, J H Hwang, C Castonguay, S L Swain, K K McKinstry

    IL-15 supports the generation of protective lung-resident memory CD4 T cells IL-15 supports the generation of protective lung-resident memory CD4 T cells, Published online: 29 November 2017; doi:10.1038/mi.2017.101 IL-15 supports the generation of protective lung-resident memory CD4 T cells

    更新日期:2017-12-15
  • Mucocutaneous IL-17 immunity in mice and humans: host defense vs. excessive inflammation
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-11-29
    J Li, J-L Casanova, A Puel

    Mucocutaneous IL-17 immunity in mice and humans: host defense vs. excessive inflammation Mucocutaneous IL-17 immunity in mice and humans: host defense vs. excessive inflammation, Published online: 29 November 2017; doi:10.1038/mi.2017.97 Mucocutaneous IL-17 immunity in mice and humans: host defense vs. excessive inflammation

    更新日期:2017-12-15
  • A dietary flavone confers communicable protection against colitis through NLRP6 signaling independently of inflammasome activation
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-11-15
    K Radulovic, S Normand, A Rehman, A Delanoye-Crespin, J Chatagnon, M Delacre, N Waldschmitt, L F Poulin, J Iovanna, B Ryffel, P Rosenstiel, M Chamaillard

    A dietary flavone confers communicable protection against colitis through NLRP6 signaling independently of inflammasome activation A dietary flavone confers communicable protection against colitis through NLRP6 signaling independently of inflammasome activation, Published online: 15 November 2017; doi:10.1038/mi.2017.87 A dietary flavone confers communicable protection against colitis through NLRP6 signaling independently of inflammasome activation

    更新日期:2017-12-15
  • Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-11-15
    H B Jijon, L Suarez-Lopez, O E Diaz, S Das, J De Calisto, M B Yaffe, M J Pittet, J R Mora, Y Belkaid, R J Xavier, E J Villablanca

    Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system, Published online: 15 November 2017; doi:10.1038/mi.2017.91 Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system

    更新日期:2017-12-15
  • Trigger-happy resident memory CD4+ T cells inhabit the human lungs
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-11-15
    A E Oja, B Piet, C Helbig, R Stark, D van der Zwan, H Blaauwgeers, E B M Remmerswaal, D Amsen, R E Jonkers, P D Moerland, M A Nolte, R A W van Lier, P Hombrink

    Trigger-happy resident memory CD4+ T cells inhabit the human lungs Trigger-happy resident memory CD4+ T cells inhabit the human lungs, Published online: 15 November 2017; doi:10.1038/mi.2017.94 Trigger-happy resident memory CD4+ T cells inhabit the human lungs

    更新日期:2017-12-15
  • Detection of HIV-1-specific gastrointestinal tissue resident CD8+ T-cells in chronic infection
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-11-15
    Brenna E Kiniry, Shengbin Li, Anupama Ganesh, Peter W Hunt, Ma Somsouk, Pamela J Skinner, Steven G Deeks, Barbara L Shacklett

    Detection of HIV-1-specific gastrointestinal tissue resident CD8+ T-cells in chronic infection Detection of HIV-1-specific gastrointestinal tissue resident CD8+ T-cells in chronic infection, Published online: 15 November 2017; doi:10.1038/mi.2017.96 Detection of HIV-1-specific gastrointestinal tissue resident CD8+ T-cells in chronic infection

    更新日期:2017-12-15
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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