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  • Identification of a human skin commensal bacterium that selectively kills Cutibacterium acnes
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-23
    Alan M. O’Neill; Teruaki Nakatsuji; Asumi Hayachi; Michael R. Williams; Robert H. Mills; David J. Gonzalez; Richard L. Gallo

    The microbiome represents a vast resource for drug discovery as its members engage in constant conflict to outcompete one another by deploying diverse strategies for survival. Cutibacterium acnes (C. acnes) is one of the most common bacterial species on human skin and can promote the common disease acne vulgaris. By employing a combined strategy of functional screening, genetics and proteomics we discovered a strain of Staphylococcus capitis (S. capitis E12) that selectively inhibited growth of C. acnes with potency greater than antibiotics commonly used in the treatment of acne. Antimicrobial peptides secreted from S. capitis E12 were identified as four distinct phenol soluble modulins acting synergistically. These peptides were not toxic to human keratinocytes and the S. capitis extract did not kill other commensal skin bacteria but was effective against C. acnes on pig skin and on mice. Overall, these data show how a member of the human skin microbiome can be useful as a biotherapy for acne vulgaris.

  • Research Techniques Made Simple: Cell Biology Methods for the Analysis of Pigmentation
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-21
    Silvia Benito-Martínez; Yueyao Zhu; Riddhi Atul Jani; Dawn C. Harper; Michael S. Marks; Cédric Delevoye

    Pigmentation of the skin and hair represents the result of melanin biosynthesis within melanosomes of epidermal melanocytes, followed by the transfer of mature melanin granules to adjacent keratinocytes within the basal layer of the epidermis. Natural variation in these processes produces the diversity of skin and hair color among human populations, and defects in these processes lead to diseases such as oculocutaneous albinism. While genetic regulators of pigmentation have been well studied in human and animal models, we are still learning much about the cell biological features that regulate melanogenesis, melanosome maturation, and melanosome motility in melanocytes, and have barely scratched the surface in our understanding of melanin transfer from melanocytes to keratinocytes. Herein, we describe cultured cell model systems and common assays that have been used by investigators to dissect these features and that will hopefully lead to additional advances in the future.

  • Is Local Production of Autoantibodies in Skin Lesions Relevant in Pemphigus?
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-21
    Hisashi Nomura; Masayuki Amagai

    Pemphigus is an autoimmune bullous disease characterized by IgG production against desmogleins. The major sites of autoantibody production are thought to be lymph nodes, spleen, and bone marrow. Previously, it has been suggested that autoreactive B cells might exist in the skin lesions in pemphigus and produce autoantibodies. In their report, Zhou et al. expanded their previous studies and reported that ectopic lymphoid-like structures were found in pemphigus skin lesions, wherein B-cell differentiation and lesional B-cell expansion might progress. This finding provides novel insights into B-cell biology in pemphigus.

  • Noncoding Variants as Genetic Contributors to Autoimmune Disease Pathogenesis
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-21
    Ellen Javier; Xiaoming Lu; Leah C. Kottyan

    Understanding the functions of disease-associated noncoding variants is essential for understanding the molecular mechanisms driving diseases with a genetic cause and for identifying therapeutic targets. Combined computational and experimental analyses have demonstrated that IRF5 is hyperactivated by a pathogenic allele of TNPO3 through long-distance chromatin looping. This finding identifies a molecular mechanism contributing to the polygenic autoimmune diseases of systemic lupus erythematosus and systemic sclerosis.

  • Spherical Nucleic Acids as Emerging Topical Therapeutics: A Focus on Psoriasis
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-21
    Emrullah Korkmaz; Louis D. Falo

    Systemically delivered targeted biologics have revolutionized the treatment of moderate-to-severe psoriasis. For milder forms of psoriasis, topical therapies, primarily corticosteroids, remain the mainstay of treatment to reduce the risks and off-target side effects associated with systemic therapies. Most newly developed biologics, including monoclonal antibodies, are structurally complex and are unable to penetrate the skin barrier. Recently developed liposomal spherical nucleic acids overcome this barrier and enable topical delivery of antisense oligonucleotides capable of specifically targeting inflammatory pathways underlying psoriasis pathogenesis.

  • Survival in Mycosis Fungoides and Sezary Syndrome: How Can We Predict Outcome?
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-21
    Julia J. Scarisbrick

    Early-stage mycosis fungoides (MF) has been associated with long survival. A recent meta-analysis including 6,279 patients with MF and Sezary syndrome found that about 10–20% of stage IB patients don’t survive 5 years, whereas patients with advanced-stage MF and Sezary syndrome have a 5-year survival chance of about 20–60%. Identifying prognostic markers to better identify those at risk of limited survival may allow improved management choices and this, coupled with newer treatments, could improve survival.

  • Mechanical Forces in the Skin: Roles in Tissue Architecture, Stability, and Function
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-07-18
    Leah C. Biggs; Christine S. Kim; Yekaterina A. Miroshnikova; Sara A. Wickström

    Tissue shape emerges from the collective mechanical properties and behavior of individual cells and the ways by which they integrate into the surrounding tissue. Tissue architecture and its dynamic changes subsequently feed back to guide cell behavior. The skin is a dynamic, self-renewing barrier that is subjected to large-scale extrinsic mechanical forces throughout its lifetime. The ability to withstand this constant mechanical stress without compromising its integrity as a barrier requires compartment-specific structural specialization and the capability to sense and adapt to mechanical cues. This review discusses the unique mechanical properties of the skin and the importance of signals that arise from mechanical communication between cells and their environment.

  • Severe Skin Permeability Barrier Dysfunction in Knockout Mice Deficient in a Fatty Acid ω-Hydroxylase Crucial to Acylceramide Production
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-07-26
    Masatoshi Miyamoto; Narumi Itoh; Megumi Sawai; Takayuki Sassa; Akio Kihara

    The skin permeability barrier is indispensable for maintaining water inside the body and preventing the invasion of pathogens and allergens; abnormalities lead to skin disorders such as atopic dermatitis and ichthyosis. Acylceramide is an essential lipid for skin barrier formation, and CYP4F22 is a fatty acid ω-hydroxylase involved in its synthesis. Mutations in CYP4F22 cause autosomal recessive congenital ichthyosis, although the symptoms vary among mutation sites and types. Here, we generated knockout mice deficient in Cyp4f39, the mouse ortholog of human CYP4F22, to investigate the effects of completely abrogating the function of the fatty acid ω-hydroxylase involved in acylceramide production on skin barrier formation. Cyp4f39 knockout mice died within 8 hours of birth. Large increases in transepidermal water loss and penetration of a dye from outside the body were observed, indicating severe skin barrier dysfunction. Histologic analyses of the epidermis revealed impairment of lipid lamella formation, accumulation of corneodesmosomes in the stratum corneum, and persistence of periderm. In addition, lipid analyses by mass spectrometry showed almost complete loss of acylceramide and its precursor ω-hydroxy ceramide. In conclusion, our findings provide clues to the molecular mechanisms of skin barrier abnormalities and the pathogenesis of ichthyosis caused by Cyp4f39 and CYP4F22 by association.

  • Targeting the Cutaneous Microbiota in Atopic Dermatitis by Coal Tar via AHR-Dependent Induction of Antimicrobial Peptides
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-07-22
    Jos P.H. Smits; Thomas H.A. Ederveen; Gijs Rikken; Noa J.M. van den Brink; Ivonne M.J.J. van Vlijmen-Willems; Jos Boekhorst; Marijke Kamsteeg; Joost Schalkwijk; Sacha A.F.T. van Hijum; Patrick L.J.M. Zeeuwen; Ellen H. van den Bogaard
  • Essential Role for Integrin-Linked Kinase in Melanoblast Colonization of the Skin
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-07-19
    Melissa Crawford; Valerie Leclerc; Kevin Barr; Lina Dagnino

    Melanocytes are pigment-producing cells found in the skin and other tissues. Alterations in the melanocyte lineage give rise to a plethora of human diseases, from neurocristopathies and pigmentation disorders to melanoma. During embryogenesis, neural crest cell subsets give rise to two waves of melanoblasts, which migrate dorsolaterally, hone to the skin, and differentiate into melanocytes. However, the mechanisms that govern colonization of the skin by the first wave of melanoblasts are poorly understood. Here we report that targeted inactivation of the integrin-linked kinase gene in first wave melanoblasts causes defects in the ability of these cells to form long pseudopods, to migrate, and to proliferate in vivo. As a result, integrin-linked kinase–deficient melanoblasts fail to populate normally the developing epidermis and hair follicles. We also show that defects in motility and dendricity occur upon integrin-linked kinase gene inactivation in mature melanocytes, causing abnormalities in cell responses to the extracellular matrix substrates collagen I and laminin 332. Significantly, the ability to form long protrusions in mutant cells in response to collagen is restored in the presence of constitutively active Rac1, suggesting that an integrin-linked kinase-Rac1 nexus is likely implicated in melanocytic cell establishment, dendricity, and functions in the skin.

  • LRG1 Promotes Keratinocyte Migration and Wound Repair through Regulation of HIF-1α Stability
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-07-22
    Ya Gao; Zhibo Xie; Chiakang Ho; Jing Wang; Qingfeng Li; Yifan Zhang; Jia Zhou

    Re-epithelialization is a complex process during skin wound healing, and cell migration is an integral part of this phenomenon. Here we identified a role for LRG1 as a key regulator of epidermal keratinocyte migration where LRG1 acts via enhancement of HIF-1α stability. We showed that LRG1 is upregulated at murine skin wound edges and that addition of recombinant human LRG1 accelerates keratinocyte migration and skin wound healing. Furthermore, we identified transcription factor ELK3 as a downstream effector of LRG1. We confirmed that elevated ELK3 levels manipulated by LRG1 can promote cell migration through upregulation of HIF-1α stability. Because hyperglycemia complicatedly affects HIF-1α stability and activation, our findings provide insights into the molecular controls of wound-associated cell migration and identify potential therapeutic targets for the treatment of chronic diabetic wounds. In conclusion, we demonstrated that LRG1 promotes wound repair through keratinocyte migration and is important for normalization of an abnormal process of diabetic wound healing where HIF-1α stability is insufficient.

  • The Phytocannabinoid (–)-Cannabidiol Operates as a Complex, Differential Modulator of Human Hair Growth: Anti-Inflammatory Submicromolar versus Hair Growth Inhibitory Micromolar Effects
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-07-29
    Imre L. Szabó; Erika Lisztes; Gabriella Béke; Kinga Fanni Tóth; Ralf Paus; Attila Oláh; Tamás Bíró
  • Ciliation index is a useful diagnostic tool in challenging spitzoid melanocytic neoplasms
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-22
    Ursula E. Lang; Rodrigo Torres; Christine Cheung; Eszter K. Vladar; Timothy H. McCalmont; Jinah Kim; Robert L. Judson-Torres

    The loss of primary cilia on melanocytes is a useful biomarker for the distinction of melanoma from conventional melanocytic nevi. It is unknown whether ciliation status is beneficial for diagnosing spitzoid tumors - a subclass of melanomas that present inherently ambiguous histology and are challenging to classify. We evaluated ciliation index (CI) in 68 cases of spitzoid tumors ranging from Spitz nevi (SN) and atypical Spitz tumors (AST) to spitzoid melanoma (SM). We found a significant decrease in CI within the SM group when compared to either the SN or AST groups. We additionally used a machine-learning based algorithm to determine the value of CI when considered in combination with other histopathologic and molecular features commonly used for diagnosis. We found that a low CI was consistently ranked as a top predictive feature in the diagnosis of malignancy. Predictive models trained on only the top four predictive features (CI, asymmetry, hyperchromatism and cytological atypia) out-performed standard histological assessment in an independent validation cohort of 56 additional cases. The results provide an alternative approach to evaluate diagnostically challenging melanocytic lesions, and further support the use of CI as an ancillary diagnostic test.

  • RNase 7 promotes sensing of self-DNA by human keratinocytes and activates an antiviral immune response.
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-21
    V. Kopfnagel; S. Dreyer; K. Baumert; M. Stark; J. Harder; K. Hofmann; M. Kleine; A. Buch; B. Sodeik; T. Werfel

    RNase 7 is one of the major antimicrobial peptides (AMPs) secreted by keratinocytes. The AMPs hBD-2 and LL-37 promote TLR9-mediated activation of human plasmacytoid dendritic cells (pDCs) by human self-DNA; however, whether keratinocytes respond in a similar way has not yet been addressed. Keratinocytes express several receptors for the detection of cytosolic DNA. Here, we investigated the activation of keratinocytes by RNase 7 in combination with human DNA. Stimulation of keratinocytes with RNase 7 and human DNA induced a strong increase of IP-10 production. Of note, stimulation of keratinocytes with hBD-2 and LL-37 in combination with DNA failed to induce IP-10 production. The production of IP-10 was mediated by the induction of the type I Interferon IFNβ and was significantly downregulated by blocking of the interferon-α/β receptor and by inhibition of STING activation. Importantly, pretreatment of keratinocytes with RNase 7 and DNA significantly reduced HSV-1 infection of human keratinocytes. Our study demonstrates that RNase 7 functions as an alarmin by converting self- DNA into a danger signal that directly activates an antiviral immune response in human keratinocytes without the involvement of pDCs.

  • Specific IgA and CLA+ T-cell IL-17 response to Streptococcus pyogenes in psoriasis
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-21
    Carmen De Jesús-Gil; Lidia Sans-de San Nicolás; Ester Ruiz-Romeu; Marta Ferran; Laura Soria-Martinez; Anca Chiriac; Antonio Celada; Ramon M. Pujol; Luis F. Santamaria-Babí

    Streptococcus pyogenes tonsillar infection is well-known to trigger and exacerbate psoriasis lesions in both guttate and plaque forms of the disease. Although mucosal and cutaneous tissues are closely involved in psoriasis pathology, the interaction between their specific immune responses has not been deeply explored. This work aims to address and characterize the presence of humoral responses against Streptococcus pyogenes in psoriasis patients and its putative association with cytokine responses detected in vitro in our psoriasis ex vivo model, based on the coculture of CLA+/- T cells with autologous epidermal cells. Psoriasis patients presented increased IgA response to S. pyogenes when compared to control subjects. Surprisingly, in plaque psoriasis patients, despite being negative for anti-streptolysin O antibody titer, IgA plasma levels against S. pyogenes correlated with CLA+ T cell dependent IL-17F response in vitro. Not association is observed for IgG levels in plaque psoriasis. Similar association is observed for IgA anti-SE and IL-17A in guttate psoriasis patients. We propose S. pyogenes specific IgA as a potential new perspective for better understanding the role of S. pyogenes in psoriasis development.

  • Molecular and Cellular Responses to the TYK2/JAK1 Inhibitor, PF 06700841, Reveal Reduction of Skin Inflammation in Plaque Psoriasis
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-21
    Karen M. Page; Mayte Suarez-Farinas; Maria Suprun; Weidong Zhang; Sandra Garcet; Judilyn Fuentes-Duculan; Xuan Li; Matthew Scaramozza; Elizabeth Kieras; Christopher Banfield; James D. Clark; Andrew Fensome; James G. Krueger; Elena Peeva

    The interleukin (IL)-23/T-helper type 17 cell axis is a target for psoriasis. The tyrosine kinase 2 (TYK2)/Janus kinase 1 (JAK1) inhibitor, PF-06700841, will directly suppress TYK2-dependent IL-12 and IL-23 signaling and JAK1-dependent signaling in cells expressing these signaling molecules, including T cells and keratinocytes. This clinical study sought to define the inflammatory gene and cellular pathways through which PF-06700841 improves the clinical manifestations of psoriasis. Patients (n=30) with moderate-to-severe psoriasis were randomized to once-daily 30 mg (n=14) or 100 mg (n=7) PF-06700841, or placebo (n=9) for 28 days. Biopsies were taken from non-lesional and lesional skin at baseline, weeks 2 and 4. Changes in the psoriasis transcriptome and genes induced by IL-17 in keratinocytes were evaluated with microarray profiling and RT-PCR. Reductions in IL-17A, IL-17F, and IL-12B mRNA were observed as early as 2 weeks and ∼70% normalization of lesional gene expression after 4 weeks. Immunohistochemistry showed significant decreases in markers of keratinocyte activation, epidermal thickness, KRT16 and Ki-67 expression, and immune cell infiltrates CD3+/CD8+ (T cells) and CD11c (dendritic cells) after 2 weeks of treatment, corresponding with improvement in histologic score. PF-06700841 improves clinical symptoms of chronic plaque psoriasis by inhibition of pro-inflammatory cytokines that require TYK2 and JAK1 for signal transduction.

  • The phosphatase regulator NIPP1 restrains chemokine-driven skin inflammation
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-21
    Iris Verbinnen; Marloes Jonkhout; Kifayathullah Liakath-Ali; Kathelijne Szekér; Mónica Ferreira; Shannah Boens; Raphael Rouget; Margareta Nikolic; Susan Schlenner; Aleyde Van Eynde; Mathieu Bollen

    NIPP1 is a ubiquitously expressed nuclear protein that regulates functions of protein Ser/Thr phosphatase-1 in cell proliferation and lineage specification. The role of NIPP1 in tissue homeostasis is not fully understood. Here we show that the selective deletion of NIPP1 in mouse epidermis resulted in epidermal hyperproliferation, a reduced adherence of basal keratinocytes and a gradual decrease in the stemness of hair follicle stem cells, culminating in hair loss. This complex phenotype was associated with chronic sterile skin inflammation and could be partially rescued by dexamethasone treatment. NIPP1-deficient keratinocytes massively expressed pro-inflammatory chemokines and immunomodulatory proteins in a cell-autonomous manner. Chemokines subsequently induced the recruitment and activation of immune cells, in particular conventional dendritic cells and Langerhans cells, accounting for the chronic inflammation phenotype. Our data identify NIPP1 as a key regulator of epidermal homeostasis and as a potential target for the treatment of inflammatory skin diseases.

  • Activated Hgf-Met signaling cooperates with oncogenic Braf to drive primary cutaneous melanomas and angiotropic lung metastases in mice
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-20
    Andreas Dominik Braun; Miriam Mengoni; Susanne Bonifatius; Thomas Tüting; Evelyn Gaffal

    Oncogenic mutations in the Braf-kinase gene represent the most frequent genomic driver in acquired melanocytic nevi and in cutaneous melanomas. It is currently thought that oncogene-induced senescence and cell cycle arrest limit the ability of oncogenic Braf to promote melanocyte proliferation in benign nevi. The molecular and cellular mechanisms that allow an oncogenic Braf mutation to fully transform melanocytes into invasively growing melanoma cells that are able to metastasize systemically are only partially understood. Here we show in a genetic mouse model that constitutively enhanced Hgf-Met signaling cooperates with oncogenic Braf to drive tumor development and metastatic spread. Activation of oncogenic Braf in mice with transgenic Hgf overexpression and an oncogenic Cdk4 germline mutation accelerated and increased the development of primary cutaneous melanomas. Primary melanomas showed considerable phenotypic heterogeneity with frequent signs of dedifferentiation. Braf activation in Hgf-Cdk4 mice also increased the number of lung metastases. Intriguingly, melanoma cells showed a pronounced angiotropic growth pattern both at the invasive front in primary tumors and in metastatic lesions of the lung. Taken together, our work supports the notion that activated Hgf-Met signaling and oncogenic Braf can cooperate in melanoma pathogenesis.

  • Uniting Discovery and Care: The Role of Pharmaceutical Companies in Research, Clinical Studies and Patient Care
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-20
    Chenyun Tan; James M. McGill; Lotus Mallbris

    In an era of increased complexity of clinical research, a demand for personalized medicine, an increasing value of diversity, a focus on digital health, and a call for patient-centricity, the discovery and development of new medicines, more than ever, is dependent on collaboration between multiple stakeholders (Figure 1).

  • IL-17E (IL-25) and IL-17A differentially affect the functions of human keratinocytes
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-18
    Julia Borowczyk; Claudia Buerger; Neschaat Tadjrischi; Justyna Drukala; Michal Wolnicki; Dawid Wnuk; Ali Modarressi; Wolf-Henning Boehncke; Nicolò Costantino Brembilla

    Our group has recently shown that keratinocyte-derived IL-17E (IL-25), one of six members of the IL-17 family, is overexpressed in lesional psoriatic skin and is involved in its pathophysiology. We show here that IL-22 enhances IL-17E production in human keratinocytes and that these cells display a complete IL-17E receptor at their surface, which expression is further induced by IL-17A, indicating a potential autocrine effect of IL-17E. Therefore, we addressed the impact of IL-17E on the function of human primary keratinocytes. IL-17E promoted the proliferation of keratinocytes in 2D and 3D cultures and caused the concomitant up-regulation of differentiation-associated gene transcripts (e.g keratin 10), while their expression was either inhibited or not changed by IL-17A. Contrary to IL-17A, IL-17E was not involved in the induction of antimicrobial proteins. Time-lapse analysis of cell movement showed that IL-17E influences cell motility increasing both cell speed and displacement. This was associated with specific changes in the actin cytoskeleton organization and the cell-substrate adhesion. No such effects were observed upon IL-17A stimulation. In summary, we identified to our knowledge previously unreported effects of IL-17E clearly distinct from IL-17A, pointing towards an important role of IL-17E in the physiology and pathophysiology of the epidermis.

  • Decreased CCN3 in Systemic Sclerosis endothelial cells contributes to impaired angiogenesis
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-16
    Pauline Henrot; François Moisan; Paôline Laurent; Pauline Manicki; Priscilla Kaulanjan-Checkmodine; Valérie Jolivel; Hamid Reza Rezvani; Vaianu Leroy; François Picard; Carine Boulon; Thierry Schaeverbeke; Julien Seneschal; Estibaliz Lazaro; Alain Taïeb; Marie-Elise Truchetet; Muriel Cario
  • A small molecule CCR2 antagonist depletes tumor macrophages and synergizes with anti-PD1 in a murine model of cutaneous T cell lymphoma (CTCL)
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-13
    Xuesong Wu; Rajinder Singh; Daniel K. Hsu; Yan Zhou; Sebastian Yu; Dan Han; Zhenrui Shi; Mindy Huynh; James J. Campbell; Sam T. Hwang
  • Calcium-inducible MAPK/AP-1 signaling drives semaphorin 3A expression in normal human epidermal keratinocytes
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-13
    Yayoi Kamata; Mitsutoshi Tominaga; Yoshie Umehara; Kotaro Honda; Atsuko Kamo; Catharina Sagita Moniaga; Eriko Komiya; Sumika Toyama; Yasushi Suga; Hideoki Ogawa; Kenji Takamori

    Epidermal keratinocytes express semaphorin (Sema) 3A, which is involved in the regulation of cutaneous innervation. However, the mechanisms underlying the intracellular signaling of Sema3A expression in keratinocytes remain unknown. We herein investigated signaling mechanisms for the induction of Sema3A expression in normal human epidermal keratinocytes (NHEKs). Sema3A expression transiently increased in calcium-stimulated NHEKs, but markedly decreased in terminally differentiated NHEKs. Sema3A mRNA mainly localized in the stratum basale and stratum suprabasale of the epidermis. The 5'-flanking region of the Sema3A gene was cloned, and a critical region for Sema3A promoter activity within -134 bp of the start codon was identified. Transcription factor binding sites, including that for activator protein (AP)-1, were found in this region. Sema3A expression was increased by the co-overexpression of JunB and Fra-2 in the presence of 0.1 or 1.4 mM calcium. The calcium-mediated transient up-regulation of Sema3A expression was significantly suppressed by mitogen-activated protein kinase [MAPK]/extracellular signal-regulated kinase [ERK] (MEK) 1/2 or AP-1 inhibitors. These results demonstrate that the calcium-mediated transient up-regulation of Sema3A in NHEKs is involved in the MEK/ERK and AP-1 signaling axis. Therefore, Sema3A mRNA may be expressed in the lower epidermis under controlled conditions by calcium via the MAPK-AP1 axis.

  • Steroid receptor RNA activator (SRA), a long noncoding RNA, activates p38, facilitates epithelial mesenchymal transformation, and experimental melanoma metastasis
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-13
    Chien-Hui Hong; Ji-Chen Ho; Chih-Hung Lee

    Melanoma metastasis signals dismal prognosis even with current checkpoint inhibitors. Long noncoding RNAs (lncRNAs) regulate dynamic metastasis in several cancers, including melanoma. We become interested in a lncRNA, SRA (steroid receptor RNA activator), because it is the first lncRNA also encoding a conserved protein SRAP and regulates progression of prostate and breast cancers. We investigated how SRA mediates melanoma proliferation, migration, invasion, EMT, and metastasis by RNA interference. The expression of SRAP was measured in melanoma tissue and in human and mouse B16 melanoma cells by immunofluorescence and PCR. The result showed that SRA knock down decreased B16 cell and A375 cell proliferation and it inhibited B16 cell migration significantly. Transwell analysis revealed that CCL21-mediated invasion was abolished in SRA-deficient B16 cells. In parallel, p38 de-phosphorylation and reciprocally phosphorylation of bRAF and MEK1/2 were present in B16-SRAi cells. Interestingly, the induction of EMT markers, β-catenin and n-cadherin, by CCL21 was reduced in B16-SRAi cells, suggesting that SRA promotes EMT process. In vivo experimental metastasis showed that B16-SRAi cells formed significantly less tumor nodules in lungs grossly and microscopically. In summary, our result showed that SRA expression is increased in melanoma tissue and that SRA mediates p38 activation, cell invasion, proliferation, regulates EMT and distant metastasis.

  • Differences in staining for neutrophil elastase and its controlling inhibitor SLPI reveal heterogeneity among neutrophils in psoriasis.
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-13
    Joanna Skrzeczynska-Moncznik; Katarzyna Zabieglo; Oktawia Osiecka; Agnieszka Morytko; Piotr Brzoza; Lukasz Drozdz; Monika Kapinska-Mrowiecka; Brice Korkmaz; Maciej Pastuszczak; Joanna Kosalka-Wegiel; Jacek Musial; Joanna Cichy

    Neutrophils are broadly classified into conventional neutrophils (PMNs) and low density granulocytes (LDGs). LDGs are better than PMNs in the generation of NETs, which may contribute to the pathology of autoimmune diseases. We hypothesized that LDGs and PMNs differ in levels of unrestrained neutrophil elastase (NE) that supports NET generation. Here, we show that individuals with psoriasis contain elevated levels of LDGs and that in contrast to PMNs, LDGs display higher staining for NE and lower staining for its inhibitor SLPI. The heterogeneity between blood-derived LDGs and PMNs was somewhat reminiscent of the differences in NE and SLPI staining patterns observed in psoriasis skin-infiltrating neutrophils. Distinctive staining for NE and SLPI in LDGs and PMNs did not result from differences in their protein levels nor manifested in higher total proteolytic activity of NE in LDGs; rather, it likely depended on different cytosolic sequestration of these proteins. The disparate profile of NE and SLPI in LDGs and PMNs coincided with altered migratory responses of these cells to cutaneous chemoattractants. Collectively, differential NE and SLPI staining identifies common attributes of both circulating and skin-infiltrating neutrophils, which may guide neutrophil migration to distinct skin regions and determine the localization of LDGs-mediated cutaneous pathology.

  • MiR-101-3p down-regulates TLR2 expression, leading to reduction in cytokines production by T. pallidum-stimulated macrophages
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2020-01-11
    Tao Huang; Jieyi Yang; Jun Zhang; Wujian Ke; Fei Zou; Chengsong Wan; Liuyuan Wang; Xiaohui Zhang; Fangwen Liang; Shuqing Mei; Qiwei Zhang; Zhili Rong; Bin Yang; Heping Zheng

    Treponema pallidum (Tp) infection-induced immune responses can cause tissue damage. However, the underlying mechanism by which Tp infection induces immune response is unclear. Recent studies suggest a regulatory role of microRNAs (miRNAs) in host immunity. We assessed whether miRNAs also have a regulatory role in immune response to Tp infection in vitro. Our results showed that miR-101-3p levels were significantly higher in peripheral blood mononuclear cells of patients with primary syphilis and those in the serofast state, while TLR2 levels were higher in syphilitic patients than in healthy controls. In vitro, stimulation of THP-1 cells with Tp increased miR-101-3p expression. Moreover, miR-101-3p reduced expression levels of TLR2 mRNA and protein in THP-1 cells via binding to the 3′ untranslated region of TLR2. Likewise, miR-101-3p inhibited production of inflammatory cytokines, including IL-1β, IL-6, TNF-α, and IL-12, in Tp-stimulated macrophages. IL-1β and IL-6 mRNA expression levels were reduced by transfection of macrophages with a TLR2-specific small interfering RNA. Conversely, overexpression of TLR2 up-regulated cytokines expression. Patients with secondary syphilis exhibited the highest levels of plasma IL-6, which were negatively correlated with miR-101-3p. In conclusion, Tp infection up-regulates miR-101-3p expression, which in turn inhibits the TLR2 signaling pathway, leading to reduced cytokines production.

  • Aryl Hydrocarbon Receptor in Cutaneous Vascular Endothelial Cells Restricts Psoriasis Development by Negatively Regulating Neutrophil Recruitment.
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-12-30
    Zhenlai Zhu; Jiaoling Chen; Yiting Lin; Chen Zhang; Wei Li; Hongjiang Qiao; Meng Fu; Erle Dang; Gang Wang

    Vascular endothelial cells (VECs) that line the interiors of blood vessels participate in physiological and inflammatory processes. All skin cell types express the aryl hydrocarbon receptor (AhR), which is involved in the pathogenesis of psoriasis. However, the role of the cutaneous VEC AhR in the pathogenesis of psoriasis remains elusive. In the present study, we found that AhR protein expression and activation were downregulated in psoriatic VECs. Furthermore, cutaneous VEC-specific AhR-knockout (AhRcVECs-KO) mice were established. Using imiquimod (IMQ) and IL-23-induced psoriasis models, we found that skin inflammation was exacerbated with excessive neutrophil recruitment in AhRcVECs-KO mice. And neutrophil neutralization alleviates exacerbated inflammation in IMQ-treated AhRcVECs-KO mice. In addition, cutaneous VECs in AhRcVECs-KO mice exhibited increased dilation and activation compared with those in control mice. Furthermore, AhR-deficient microvascular endothelial cells stimulated by proinflammatory cytokines showed increased ICAM-1 expression in vivo and in vitro, which may have facilitated neutrophil recruitment. In summary, our study demonstrates that AhR in dermal VECs restricts psoriasis development by negatively regulating neutrophil recruitment, thereby providing previously unreported insight into the pathogenesis of psoriasis.

  • Kallikrein 7 promotes atopic dermatitis-associated itch independently of skin inflammation
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-12-26
    Changxiong J. Guo; Madison R. Mack; Landon K. Oetjen; Anna M. Trier; Martha L. Council; Ana B. Pavel; Emma Guttman-Yassky; Brian S. Kim; Qin Liu

    Atopic dermatitis (AD) is a highly prevalent, itchy inflammatory skin disorder that is thought to arise from a combination of defective skin barrier and immune dysregulation. Kallikreins (KLK), a family of serine proteases with a diverse array of homeostatic functions including skin desquamation and innate immunity, are speculated to contribute to AD pathogenesis. Their precise role in AD, however, has not been clearly defined. In this study, unbiased RNA-seq analyses identified KLK7 as the most abundant and differentially expressed KLK in both human AD and murine AD-like skin. Further, in mice, Klk7 expression was localized to the epidermis in both steady state and inflammation. However, KLK7 was dispensable for the development of AD-associated skin inflammation. Instead, KLK7 was selectively required for AD-associated chronic itch. Even without alleviation of skin inflammation, KLK7-deficient mice exhibited significantly attenuated scratching, compared to controls, after AD-like disease induction. Collectively, our findings indicate that KLK7 promotes AD-associated itch independently from skin inflammation, and reveal a previously unrecognized epidermal-neural mechanism of AD itch.

  • Melanin has a small inhibitory effect on cutaneous vitamin D synthesis: a comparison of extreme phenotypes
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-12-26
    Antony R. Young; Kylie A. Morgan; Tak-Wai Ho; Ngozi Ojimba; Graham I. Harrison; Karl P. Lawrence; Nihull Jakharia-Shah; Hans Christian Wulf; J Kennedy Cruickshank; Peter A. Philipsen

    Epidemiology suggests that melanin inhibits cutaneous vitamin D3 synthesis by solar ultraviolet radiation (UVR). Laboratory investigations assessing the impact of melanin on vitamin D production have given contradictory results. We determined the effect of melanin on vitamin D3 photosynthesis in healthy young volunteers (n=102) of Fitzpatrick skin types II-VI (white to black). Participants, irrespective of skin type, were exposed to the same sub-erythemal UVR dose, to 85% body surface area, using solar simulated UVR or narrowband UVB (311nm). This was repeated 5 times with intervals of 3-4 days between UVR exposures. Blood was taken before, during and after the irradiations and assessed for serum 25(OH)D3 as a marker of vitamin D3 status. Linear UVR dose-dependent increases in 25(OH)D3 were highly significant (p ≤ 7.7 x 10-11). The ratios of regression slopes of the different skin type groups were compared, and only skin type II was significantly steeper than the other groups. Comparisons between extreme skin types II and VI showed melanin inhibition factors of about 1.3–1.4, depending on UVR source. We conclude that the inhibitory effect of melanin on vitamin D3 synthesis is small, compared to erythema, but that this difference may be sufficient to explain the epidemiological data.

  • Reduction in human epidermal Langerhans cells with age is associated with decline in CXCL14-mediated recruitment of CD14+ monocytes
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-12-25
    Tatsuya Hasegawa; Zhaoyi Feng; Zhiyu Yan; Kenneth H. Ngo; Junichi Hosoi; Shadmehr Demehri
  • NKG2D defines a subset of skin effector memory CD8 T cells with pro-inflammatory functions in vitiligo
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-12-24
    Clément Jacquemin; Christina Martins; Fabienne Lucchese; Denis Thiolat; Alain Taieb; Julien Seneschal; Katia Boniface

    Vitiligo is an autoimmune disease that results from the loss of melanocytes, associated with skin infiltration of CD8+ effector memory T (TEM) cells with a Tc1 skewed immune response. Natural killer group 2D (NKG2D) is an activating receptor found on immune cells, in particular NK and activated CD8+ T cells, that is able to produce a high amount of IFN-γ. Here we found that NKG2D expression was increased in vitiligo skin CD8+ TEM cells and was promoted by IL-15. Phenotypic and functional analyses showed that NKG2D+ CD8+ skin TEM cells displayed an activated phenotype and produced elevated levels of both IFN-γ and TNF-α. Additional experiments revealed that vitiligo skin dendritic cells (DCs) expressed the NKG2D ligands MICA-MICB, and in vitro experiments showed that these ligands could be induced on DCs by IFN-α. Cultures of IFN-α stimulated DCs with skin NKG2D+ CD8+ T cells potentiated the production of type-1 cytokines, that was next inhibited by blocking the NKG2D/MICA-MICB interaction. These data show that NKG2D is a potential marker of pathogenic skin CD8+ TEM cells during vitiligo. Therefore, targeting NKG2D could be an attractive strategy in vitiligo, a disease for which there is a strong need of innovative treatments.

  • Tussilagonone ameliorates psoriatic features in keratinocytes and imiquimod-induced psoriasis-like lesions in mice via Nrf2 activation
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-12-23
    Joohee Lee; Kwangho Song; Paul Hiebert; Sabine Werner; Tae-Gyun Kim; Yeong Shik Kim
  • T-Type calcium channels as potential therapeutic targets in vemurafenib-resistant BRAFV600E melanoma
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-12-23
    C. Barceló; P. Sisó; O. Maiques; S. García-Mulero; R. Sanz-Pamplona; R. Navaridas; C. Megino; I. Felip; I. Urdanibia; N. Eritja; X. Soria; J.M. Piulats; R.M. Penin; X. Dolcet; X. Matías-Guiu; R.M. Martí; A. Macià

    Melanoma is a malignant neoplasia that is highly resistant to chemotherapy and radiotherapy and is associated with poor prognosis in advanced stage. Targeting melanoma that harbors the common BRAFV600E mutation with kinase inhibitors, such as vemurafenib, reduces tumor burden, but these tumors frequently acquire resistance to these drugs. We previously proposed that T-type calcium channel (TTCC) expression may serve as a biomarker for melanoma progression and prognosis, and we showed that TTCC blockers reduce migration and invasion rates due to autophagy blockade only in BRAFV600E-mutant melanoma cells. Here, we demonstrated that high expression of the TTCC Cav3.1 isoform is related to autophagic status in vemurafenib-resistant BRAFV600E-mutant melanoma cells and human biopsies, and in silico analysis revealed an enrichment of Cav3.1 expression in post-treatment melanomas. We also demonstrated that the TTCC blocker mibefradil induces apoptosis and impairs migration/invasion via inhibition of autophagy in resistant melanoma cells and mouse xenograft models. Moreover, we identified an association between PTEN status and Cav3.1 expression in these cells as a marker of sensitivity to combination therapy in resistant cells. Together, our results suggest that TTCC blockers offer a potential targeted therapy in resistant BRAFV600E-mutant melanoma and a therapeutic strategy to reduce progression toward BRAFi resistance.

  • Staphylococcus aureus colonization is increased on lupus skin lesions and is promoted by interferon-mediated barrier disruption
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-12-23
    Sirisha Sirobhushanam; Navya Parsa; Tamra J. Reed; Celine C. Berthier; Mrinal K. Sarkar; Grace A. Hile; Lam C. Tsoi; Josh Banfield; Craig Dobry; Alexander R. Horswill; Johann E. Gudjonsson; J. Michelle Kahlenberg

    Cutaneous inflammation is recurrent in systemic lupus erythematosus (SLE), yet mechanisms that drive cutaneous inflammation in SLE are not well-defined. Type I IFNs are elevated in non-lesional SLE skin and promote inflammatory responses. Staphylococcus aureus, known to induce IFN production, could play a role in cutaneous inflammation in SLE. We show here that active cutaneous lupus erythematosus (CLE) lesions are highly colonized (∼50%) by S. aureus. To define the impact of IFNs on S. aureus colonization, we examined the effects of type I and type II IFNs on S. aureus adherence and invasion. An increase in adherent S. aureus was observed after exposure to both IFNα and γ whereas IFNγ appeared to inhibit invasion of S. aureus. CLE lesional skin microarray data and RNA-seq data from SLE keratinocytes identified repression of barrier gene expression, such as filaggrin and loricrin, and SLE keratinocytes exhibited increased S. aureus-binding integrins. These SLE-associated changes could be replicated by IFN treatment of keratinocytes. Further, SLE keratinocytes exhibited increased binding to S. aureus. Together, these data suggest that chronic exposure to IFNs induces barrier disruption that allows for higher S. aureus colonization in SLE skin.

  • Inactivation of the cytoprotective major vault protein by caspase-1 and -9 in epithelial cells during apoptosis
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-12-23
    Serena Grossi; Gabriele Fenini; Tobias Kockmann; Paulina Hennig; Michela Di Filippo; Hans-Dietmar Beer

    Inflammasome activation induces caspase-1-dependent secretion of the proinflammatory cytokine IL-1β. In addition, caspase-1 activates gasdermin D (GSDMD) in immune cells causing pyroptosis, a lytic type of cell death. In contrast, UVB irradiation of human primary keratinocytes (HPKs) induces NLRP1 inflammasome activation, cytokines secretion and caspase-1-dependent apoptosis, rather than pyroptosis. Here, we addressed the molecular mechanisms underlying the role of caspase-1 in UVB-induced cell death of HPKs. We show that GSDMD is a poor substrate of caspase-1 in HPKs and that its activation upon UVB irradiation supports secretion of IL-1β. We screened for novel substrates of caspase-1 by a mass spectrometry-based approach and identified the specific cleavage of major vault protein (MVP) at D441 by caspase-1 and -9. MVP is the main component of vaults, highly conserved ribonucleoprotein particles, whose functions are poorly understood. Cleavage of MVP is a common event occurring in HPKs and fibroblasts undergoing apoptosis induced by different stimuli. In contrast, MVP cleavage could not be detected in pyroptotic cells. Cleavage of MVP by caspase-1/-9 inactivates this cytoprotective protein. These results demonstrate a pro-apoptotic activity of caspase-1 and a crosstalk with caspase-9 upon inactivation of the cytoprotective MVP in apoptotic epithelial cells.

  • Role of the Complement Pathway in Inflammatory Skin Diseases: A Focus on Hidradenitis Suppurativa
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-12-20
    Mondana H. Ghias; Michael J. Hyde; Lewis E. Tomalin; B. Paul Morgan; Afsaneh Alavi; Michelle A. Lowes; Vincent Piguet

    Although the role of immune dysregulation in hidradenitis suppurativa (HS) has yet to be elucidated, recent studies identified several complement abnormalities in patients with HS. The complement system serves a critical role in the modulation of immune response and regulation of cutaneous commensal bacteria. Complement is implicated in several inflammatory skin diseases including systemic lupus erythematosus, angioedema, pemphigus, bullous pemphigoid, and HS. A model of HS pathogenesis is proposed, integrating the role of commensal bacteria, cutaneous immune responses, and complement dysregulation. The role of complement in disease pathogenesis has led to the development of novel anticomplement agents and clinical trials investigating the efficacy of such treatments in HS.

  • Research Techniques Made Simple: Cutaneous Colorimetry: A Reliable Technique for Objective Skin Color Measurement
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-12-18
    Bao Chau K. Ly; Ethan B. Dyer; Jessica L. Feig; Anna L. Chien; Sandra Del Bino

    Skin color evaluation contributes to assessment of an individual’s cutaneous phenotype. Skin color changes provide important clues to disease progression or treatment response. Skin color is also a predictor of skin cancer risk. Melanin pigment, blood flow, skin thickness, and photoaging contribute to skin color. Melanin, hemoglobin, bilirubin, and carotene are the primary chromophores of skin color. Their concentrations vary depending on the individual’s phenotype, anatomic location, external insults of chemical irritants and UVR, and physiological changes. The evaluation and perception of skin color are often subjective. Objective quantification of skin color can be achieved with colorimetric devices such as tristimulus colorimeters. These devices compute the intensity of light reflected from skin and correlate with pigmentation and erythema. Cutaneous color and color changes can be quantified under color organization systems, such as the CIELAB color space, which is standardized by the Commission Internationale de l’Eclairage (CIE). The CIELAB expresses color’s lightness, red/green intensity, and yellow/blue intensity, as L*, a*, and b* values, respectively. Additionally, skin color’s full spectral characteristics and cutaneous physiology can be measured with spectrophotometers. This article outlines basic principles of the CIELAB color system and how to optimally use colorimetric devices as a skin research tool.

  • IL-17A Softens the Skin: Antifibrotic Properties of IL-17A in Systemic Sclerosis
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-12-18
    Chang Zeng; J. Michelle Kahlenberg; Johann E. Gudjonsson

    IL-17A is abundant in scleroderma skin, but its pathologic role has remained unclear. In the Journal of Investigative Dermatology, Dufour et al. (2020) demonstrate a new role for IL-17A as an antifibrotic agent in scleroderma through modulation of keratinocyte responses to transforming growth factor-β and shifting of fibroblast responses from profibrotic to antifibrotic.

  • Targeting T2 Inflammation by Dupilumab Impacts on the Microbiomic “Ménage à Trois” of Atopic Dermatitis
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-12-18
    Thomas Bieber

    Dupilumab leads to an improvement of the dysbiosis in lesional and non-lesional skin in atopic dermatitis (AD). Although the causal relationship between inflammation and dysbiosis remains unclear, strategies to normalize microbiome composition remain a relevant approach in AD. How and when to best individually impact on the microbiome to improve AD in the long-term and potentially modify disease is worthy of additional exploration.

  • Human against Machine? Machine Learning Identifies MicroRNA Ratios as Biomarkers for Melanoma
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-12-18
    Melody H. Shellman; Yiqun G. Shellman

    Identification of quantitative molecular biomarkers to distinguish melanoma from nevi is highly desirable. Expressions of microRNAs (miRNAs) are promising candidates but lack consensus in many studies. Torres et al. (2020) utilized a machine learning pipeline to identify miRNA ratios as strong biomarkers. Results indicate that machine learning, although powerful, requires human input to identify high quality biomarker signatures.

  • Shifting Paradigms in Allergic Contact Dermatitis: The Role of Innate Immunity
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-05-14
    Adam K. Brys; Larissa G. Rodriguez-Homs; Jutamas Suwanpradid; Amber Reck Atwater; Amanda S. MacLeod

    The role of the innate immune system in allergic contact dermatitis (ACD) has traditionally been confined to the initial antigen sensitization phase. However, more recent findings have shown the role of innate immunity in additional aspects of ACD, including the effector phase of the classic type IV hypersensitivity reaction. As a result, the precise immunologic mechanisms mediating ACD are more complex than previously believed. The aim of this review is to provide insight into recent advances in understanding the role of the innate immune system in the pathogenesis of ACD, including novel mechanistic roles for macrophages, innate lymphoid cells, natural killer cells, innate γδ T cells, and other signaling molecules. These insights provide new opportunities for therapeutic intervention in ACD.

  • Harnessing the Power of Regenerative Therapy for Vitiligo and Alopecia Areata
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-06-10
    Chauncey C. Barbulescu; Nathaniel B. Goldstein; Dennis R. Roop; David A. Norris; Stanca A. Birlea

    Vitiligo and alopecia areata (AA) are common autoimmune conditions characterized by white spots on the skin (vitiligo) and bald spots on the scalp (AA), which significantly impact patients’ lives by damaging their appearance and function. Melanocytes are the target of immune destruction in vitiligo and are hypothesized to be the site of immune attack in AA. This inflammatory process can be partially reversed by immunosuppressive drugs. Both conditions demonstrate regenerative components that are just now being identified. In this review, we focus on the regenerative medicine aspects of vitiligo and AA, using experimental data from human, mouse, and in vitro models, summarizing the key pathways involved in repopulation of the epidermis with melanocytes in vitiligo and in regrowth of hair follicles in AA. We also discuss treatments that may activate these pathways. Of the regenerative treatments, JAK inhibitors and bimatoprost stimulate repopulation of depleted cells in both diseases, intralesional injections of autologous concentrated platelet-rich plasma and minoxidil showed some benefit in AA, and phototherapy with narrowband UVB was shown to be effective especially in vitiligo. Finally, we discuss future treatments based on the mobilization of stem cells to regenerate anagen hair follicles in AA and intraepidermal melanocytes in vitiligo.

  • Second Primary Cancers in Patients with Invasive and In Situ Squamous Cell Skin Carcinoma, Kaposi Sarcoma, and Merkel Cell Carcinoma: Role for Immune Mechanisms?
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-07-06
    Subhayan Chattopadhyay; Akseli Hemminki; Asta Försti; Kristina Sundquist; Jan Sundquist; Kari Hemminki

    Second primary cancers (SPCs) are becoming a common cancer entity, which may interfere with survival in relatively benign first primary cancers. We examined the hypothesis that immune dysfunction may contribute to SPCs by assessing SPCs associated with known immune responsive skin cancers, invasive and in situ squamous cell carcinoma, Kaposi sarcoma, and Merkel cell carcinoma. Cancers were identified from the Swedish Cancer Registry from the year 1958 to 2015. Standardized relative risks were calculated bidirectionally for any SPC after skin cancer and for skin cancer as SPC. Over 80,000 first primary cancers were identified for each invasive and in situ squamous cell carcinoma of the skin. Bidirectional increased risks were observed for 26 cancers associated with invasive skin cancer; the Spearman rank correlation was 0.72 (P = 4.6 × 10–5). The highest bidirectional relative risks were for invasive and in situ skin cancer as SPCs (14.59 and 16.71, respectively). Remarkably high risks for second in situ squamous cell carcinoma of the skin were found after Kaposi sarcoma (685.68) and Merkel cell carcinoma (117.23). The high systematic bidirectional risks between immune responsive skin cancers and most other cancers suggest that immune suppression is a key mechanism contributing to an increased risk of SPCs.

  • MCPyV Large T Antigen-Induced Atonal Homolog 1 Is a Lineage-Dependency Oncogene in Merkel Cell Carcinoma
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-07-05
    Kaiji Fan; Jan Gravemeyer; Cathrin Ritter; Kashif Rasheed; Thilo Gambichler; Ugo Moens; Masahiro Shuda; David Schrama; Jürgen C. Becker

    Despite the fact that the transcription factor ATOH1 is a master regulator of Merkel cell development, its role in Merkel cell carcinoma (MCC) carcinogenesis remains controversial. Here, we provide several lines of evidence that ATOH1 is a lineage-dependent oncogene in MCC. Luciferase assays revealed binding of ATOH1 and subsequent activation to the promoter of miR-375, which is one of the most abundant microRNAs in MCCs. Overexpression of ATOH1 in variant MCC cell lines and fibroblasts induced miR-375 expression, whereas ATOH1 knockdown in classical MCC cell lines reduced miR-375 expression. Moreover, ATOH1 overexpression in these cells changed their growth characteristics from adherent to suspension and/orspheroidal growth, that is, resembling the neuroendocrine growth pattern of classical MCC cell lines. Notably, ectopic expression of different Merkel cell polyomavirus (MCPyV)-derived truncated large T antigens induced ATOH1 expression in fibroblasts, which was paralleled by miR-375 expression and similar morphologic changes. In summary, MCPyV-associated carcinogenesis is likely to induce the characteristic neuroendocrine features of MCC via induction of ATOH1; thus, ATOH1 can be regarded as a lineage-dependent oncogene in MCC.

  • CENPV Is a CYLD-Interacting Molecule Regulating Ciliary Acetylated α-Tubulin
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-06-29
    Elena Chiticariu; Alexandre Regamey; Marcel Huber; Daniel Hohl

    CYLD is a deubiquitylase with tumor suppressor functions, first identified in patients with familial cylindromatosis. Despite many molecular mechanisms in which a function of CYLD was reported, affected patients only develop skin appendage tumors, and their precise pathogenesis remains enigmatic. To elucidate how CYLD contributes to tumor formation, we aimed to identify molecular partners in keratinocytes. By using yeast two-hybrid, coprecipitation, and proximity ligation experiments, we identified CENPV as a CYLD-interacting partner. CENPV, a constituent of mitotic chromosomes associating with cytoplasmic microtubules, interacts with CYLD through the region between the third cytoskeleton-associated protein–glycine domain and the active site. CENPV is deubiquitylated by CYLD and localizes in interphase to primary cilia where it increases the ciliary levels of acetylated α-tubulin. CENPV is overexpressed in basal cell carcinoma. Our results support the notion that centromeric proteins have functions in ciliogenesis.

  • Rac-Dependent Signaling from Keratinocytes Promotes Differentiation of Intradermal White Adipocytes
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-07-24
    Takehiko Ueyama; Megumi Sakuma; Mio Nakatsuji; Tatsuya Uebi; Takeshi Hamada; Atsu Aiba; Naoaki Saito
  • Genome-Wide Analysis Reveals Zinc Transporter ZIP9 Regulated by DNA Methylation Promotes Radiation-Induced Skin Fibrosis via the TGF-β Signaling Pathway
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-06-27
    Yuyou Qiu; Yiying Gao; Daojiang Yu; Li Zhong; Weichao Cai; Jiang Ji; Fenghao Geng; Guangyu Tang; Huojun Zhang; Jianping Cao; Jie Zhang; Shuyu Zhang
  • IL-17A Dissociates Inflammation from Fibrogenesis in Systemic Sclerosis
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-07-03
    Aleksandra Maria Dufour; Julia Borowczyk-Michalowska; Montserrat Alvarez; Marie-Elise Truchetet; Ali Modarressi; Nicolò Costantino Brembilla; Carlo Chizzolini

    IL-17A is abundant in scleroderma but its role in fibrogenesis is controversial. We interrogated the role of IL-17A in extracellular matrix deposition and inflammation by investigating its effects on keratinocytes and fibroblasts cross-talk and in organotypic skin cultures. Keratinocyte-conditioned media of resting, IL-17A-, and/or transforming growth factor-β-primed primary keratinocytes were used to stimulate healthy donors and scleroderma fibroblasts. Alternatively, organotypic cultures of full human skin were challenged with these cytokines. Keratinocyte-conditioned media tilted the balance of col-I to matrix metalloproteinase-1 production by fibroblasts in favor of matrix metalloproteinase-1, significantly more so in healthy donors than in scleroderma, resulting in enhanced extracellular matrix turnover, further increased by IL-17A. In organotypic skin, transforming growth factor-β induced an extensive pro-fibrotic gene signature, including the enhanced expression of several collagen genes associated with Wnt signaling. IL-17A strongly promoted the expression of pro-inflammatory genes, with no direct effects on collagen genes, and attenuated Wnt signaling induced by transforming growth factor-β. In this model, at the protein level, IL-17A significantly decreased col-I production. Our data strongly support a pro-inflammatory and antifibrogenic activity of IL-17A in the context of keratinocyte-fibroblast interaction and in full skin. These data help in directing and interpreting targeted therapeutic approaches in scleroderma.

  • Understanding Curly Hair Mechanics: Fiber Strength
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-07-19
    Elsabe Cloete; Nonhlanhla P. Khumalo; Malebogo N. Ngoepe

    The relationship between the geometric and mechanical profiles of hair fibers has been studied, with special focus on curly samples. Incidental observations pointed to a significantly different viscoelastic character with varying curliness. Further investigations confirmed initial observations, showing an initial distinct toe region behavior for curly fibers on the stress-strain plot, which is absent for straight fibers. This behavior suggested a difference in the viscoelastic nature of the curly fiber that is linked to mechanical energy stored in the fiber. Results also suggest that the strength of hair depends on two main components, and further pointed out that de facto methods of tensile testing may erode curly fiber strength during preparation. The main outcome of this study is that the tensile strength (σT) of hair fibers is composed of two (rather than one main) components, namely the toe region (σt) and the elastic region (σε), so that: σT=σt+σε. For noncurly fibers, the greatest part of fiber strength is derived from σε, while σt ≈ 0. For curly fibers, σt (i.e., springiness) adds significantly to the overall strength, even though σε remains the major contributor. Although these results require validation in larger studies, they are significant in the current understanding of curly hair. Also, they may represent a fundamental shift from the current understanding of tensile testing of human hair in general.

  • Human Mesenchymal Stromal Cells Engineered to Express Collagen VII Can Restore Anchoring Fibrils in Recessive Dystrophic Epidermolysis Bullosa Skin Graft Chimeras
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-07-19
    Anastasia Petrova; Christos Georgiadis; Roland A. Fleck; Leanne Allison; John A. McGrath; Francesco Dazzi; Wei-Li Di; Waseem Qasim

    Recessive dystrophic epidermolysis bullosa (RDEB) is a debilitating genodermatosis caused by loss-of-function mutations in COL7A1 encoding type VII collagen (C7), the main component of anchoring fibrils at the dermal–epidermal junction. With no curative treatments presently available, retrovirally transduced autologous epidermal grafts and intradermal lentivirally engineered fibroblast injections are being investigated. Alternative approaches aim to infuse allogeneic mesenchymal stromal cells (MSCs) to provide a more generalized treatment for RDEB. We investigated whether healthy human MSCs could be engineered to overexpress C7 and correct RDEB in a human:murine chimeric model. Initially, engineered MSCs incorporated ex vivo into RDEB grafts, their presence confirmed by fluorescence in situ hybridization, revealed recovery of function of the dermal–epidermal junction with no signs of blister formation. Importantly, the detection of anchoring fibrils by transmission electron microscopy corroborated structural recovery. Next, MSCs cotransduced to express C7 and luciferase were delivered intradermally into grafted RDEB skin, resulting in localized MSC persistence with deposition of de novo C7 at the site. Notably, C7 expression was sufficient to restore anchoring fibril density to normal levels. In contrast, intravenously injected engineered MSCs were undetectable within grafts and lacked anchoring fibril reconstitution. Our data suggest that although localized correction may be achievable using engineered MSCs, strategies for systemic administration require further modeling.

  • E-Cadherin is Dispensable to Maintain Langerhans Cells in the Epidermis
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-06-28
    Anna Brand; Nathalie Diener; Sonja P. Zahner; Christoph Tripp; Ronald A. Backer; Khalad Karram; Aimin Jiang; Ira Mellman; Patrizia Stoitzner; Björn E. Clausen

    The cell adhesion molecule E-cadherin is a major component of adherens junctions and marks Langerhans cells (LC), the only dendritic cell (DC) population of the epidermis. LC form a dense network and attach themselves to the surrounding keratinocytes via homophilic E-cadherin binding. LC activation, mobilization, and migration require a reduction in LC E-cadherin expression. To determine whether E-cadherin plays a role in regulating LC homeostasis and function, we generated CD11c-specific E-cadherin knockout mice (CD11c-Ecaddel). In the absence of E-cadherin−mediated cell adhesion, LC numbers remained stable and similar as in control mice, even in aged animals. Intriguingly, E-cadherin−deficient LC displayed a dramatically changed morphology characterized by a more rounded cell body and fewer dendrites than wild-type cells. Nevertheless, maturation and migration of LC lacking E-cadherin was not altered, neither under steady-state nor inflammatory conditions. Accordingly, CD11c-Ecaddel and control mice developed comparable contact hypersensitivity reactions and imiquimod-triggered psoriatic skin inflammation, indicating that E-cadherin on LC does not influence their ability to orchestrate T cell-mediated immunity. In conclusion, our data demonstrate that E-cadherin is dispensable to maintain LC in the epidermis and does not regulate LC maturation, migration, and function.

  • IL-20-Receptor Signaling Delimits IL-17 Production in Psoriatic Inflammation
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-06-26
    Hye-Lin Ha; Hongshan Wang; Estefania Claudio; Wanhu Tang; Ulrich Siebenlist

    IL-17 cytokines, in particular IL-17A, are critical effectors in psoriasis. Antibodies that block IL-17A are highly efficacious in treating psoriasis. Likewise, disruption of IL-17 cytokines signaling, such as via the loss of the adaptor CIKS/Act1, ameliorates inflammation in mouse models of psoriasis. IL-17A promotes a cascade of effects, including the robust production of IL-19 in both humans and mice. IL-19, along with IL-20 and IL-24, signal via IL-20 receptors and comprise a subgroup within the IL-10 cytokine family. The role of these three cytokines in psoriasis is unresolved. They have been linked to inflammatory processes, including psoriatic pathology, but these cytokines have also been reported to suppress inflammation in other contexts. In this study, we demonstrate that signaling via IL-20 receptors, including in response to IL-19, delimited aspects of imiquimod-induced psoriatic inflammation. IL-20 receptor signaling suppressed the dermal production of the CCL2 chemokine and thereby reduced CCL-2-driven infiltration of inflammatory cells into the dermis, including IL-17A-producing γδT cells. This constitutes a negative feedback, since IL-17A strongly induces IL-19 in keratinocytes. The effects of IL-17 cytokines in this inflammatory setting are dynamic; they are central to the development of both dermal and epidermal hallmarks of psoriasis but also initiate a path to mitigate inflammatory damage.

  • The Long Noncoding RNA UCA1 Negatively Regulates Melanogenesis in Melanocytes
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-07-02
    Shiyao Pei; Jing Chen; Jianyun Lu; Shuanghai Hu; Ling Jiang; Li Lei; Yujie Ouyang; Chuhan Fu; Yufang Ding; Si Li; Liyang Kang; Lihua Huang; Hong Xiang; Rong Xiao; Qinghai Zeng; Jinhua Huang

    The long noncoding RNA UCA1 was first discovered in bladder cancer and is known to regulate the proliferation and migration of melanoma. However, its role in melanogenesis is unclear. In this study, we aimed to explore the role and mechanism of UCA1 in melanogenesis. Our findings showed that the expression of UCA1 was negatively correlated with melanin content in melanocytes and pigmented nevus. Overexpression of UCA1 in melanocytes decreased melanin content and the expression of melanogenesis-related genes, whereas knockdown of UCA1 in melanocytes had the opposite effect. High-throughput sequencing revealed that microphthalmia-associated transcription factor (MITF), an important transcription factor affecting melanogenesis, was also negatively correlated with the expression of UCA1. Furthermore, the transcription factor CRE-binding protein (CREB), which promotes MITF expression, was negatively regulated by UCA1. The cAMP/protein kinase A (PKA), extracellular signal–regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) signaling pathways, which are upstream of the CREB/MITF/melanogenesis axis, were activated or inhibited in response to silencing or enhancing UCA1 expression, respectively. In addition, enhanced UCA1 expression downregulates the expression of melanogenesis-related genes induced by UVB in melanocytes. In conclusion, UCA1 may negatively regulate the CREB/MITF/melanogenesis axis through inhibiting the cAMP/PKA, ERK, and JNK signaling pathways in melanocytes. UCA1 may be a potential therapeutic target for the treatment of pigmented skin diseases.

  • Variation in Cutaneous Patterns of Melanomagenesis According to Germline CDKN2A/CDK4 Status in Melanoma-Prone Families
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-07-18
    Michael R. Sargen; Ruth M. Pfeiffer; Xiaohong R. Yang; Margaret A. Tucker; Alisa M. Goldstein

    CDKN2A and CDK4 are well-established melanoma susceptibility genes, but their effect on tumor location and distribution is unknown. We used a case–case study design to assess for differences in tumor location between mutation carriers (CDKN2A = 141 patients, 348 melanomas; CDK4 = 15 patients, 54 melanomas) and noncarriers (104 patients, 157 melanomas) in US melanoma-prone families. Associations between groups were assessed with chi-square tests. Odds ratios (ORs) for tumor location were adjusted for diagnosis age, gender, and superficial spreading subtype. Models included random effects to account for within individual and family correlations. Compared with having a truncal melanoma, CDK4 (vs. noncarriers: lower extremities OR = 14.5, 95% confidence interval [CI] = 5.02–42.0, P < 0.001; upper extremities OR = 6.88, 95% CI = 2.37–19.9, P < 0.001; head and neck OR = 18.6, 95% CI = 4.04–85.2, P < 0.001) and CDKN2A (vs. noncarriers: lower extremities OR = 3.01, 95% CI = 1.56–5.82, P < 0.05; upper extremities OR = 1.91, 95% CI = 1.03–3.52, P < 0.05; head and neck OR = 5.40, 95% CI = 2.10–13.9, P < 0.001) carriers had higher odds of developing melanoma at all other sites. Similar findings were observed for analyses stratified by gender, age, and first versus subsequent melanoma diagnoses. Further studies are needed to understand the biology underlying these genotype-associated patterns of tumor development, which could provide new insights into melanoma treatment and prevention.

  • Bacteriophage of the Skin Microbiome in Patients with Psoriasis and Healthy Family Controls
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-06-24
    Hailun Wang; Henry H. Chan; Michael Y. Ni; Wendy W. Lam; W.M. Mandy Chan; Herbert Pang

    The bacteriophage (phage) component of the skin microbiome in patients with psoriasis has not been systematically explored. The purpose of this study is to investigate phage and bacterial components of the skin microbiome in patients with psoriasis and in healthy family controls. Lesional skin swabs of four different locations (elbow, forearm, knee, and scalp) were taken from patients with psoriasis. Healthy skin swabs of matched locations were taken from contralateral non-lesional skin and healthy family controls. Skin microbiomes were investigated using next-generation shotgun metagenomics sequencing. 81 skin microbiome samples (27 lesional skin samples and 54 healthy skin samples from contralateral non-lesional skin and family controls) obtained from 16 subjects with psoriasis and 16 matched family controls were sequenced and analyzed. Among phage species with abundant host bacteria, two significantly differential abundant phage species, Acinetobacter phage Presley and Pseudomonas phage O4 (adjusted P < 0.05), between psoriasis lesional skin and healthy skin were identified. Samples with high levels of these phage species had their host bacteria abundance suppressed (P = 0.03 and P < 0.001). Differential phage composition between lesional skin in patients with psoriasis and healthy skin from contralateral non-lesional sites and family controls, as well as the suppression of bacteria host of the respective phage, suggest possible avenues for probiotic phage therapeutics.

  • IL-4Rα Blockade by Dupilumab Decreases Staphylococcus aureus Colonization and Increases Microbial Diversity in Atopic Dermatitis
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-06-25
    Chris Callewaert; Teruaki Nakatsuji; Rob Knight; Tomasz Kosciolek; Alison Vrbanac; Paul Kotol; Marius Ardeleanu; Thomas Hultsch; Emma Guttman-Yassky; Robert Bissonnette; Jonathan I. Silverberg; James Krueger; Alan Menter; Neil M.H. Graham; Gianluca Pirozzi; Jennifer D. Hamilton; Richard L. Gallo

    Dupilumab is a fully human antibody to interleukin-4 receptor α that improves the signs and symptoms of moderate to severe atopic dermatitis (AD). To determine the effects of dupilumab on Staphylococcus aureus colonization and microbial diversity on the skin, bacterial DNA was analyzed from swabs collected from lesional and nonlesional skin in a double-blind, placebo-controlled study of 54 patients with moderate to severe AD randomized (1:1) and treated with either dupilumab (200 mg weekly) or placebo for 16 weeks. Microbial diversity and relative abundance of Staphylococcus were assessed by DNA sequencing of 16S ribosomal RNA, and absolute S. aureus abundance was measured by quantitative PCR. Before treatment, lesional skin had lower microbial diversity and higher overall abundance of S. aureus than nonlesional skin. During dupilumab treatment, microbial diversity increased and the abundance of S. aureus decreased. Pronounced changes were seen in nonlesional and lesional skin. Decreased S. aureus abundance during dupilumab treatment correlated with clinical improvement of AD and biomarkers of type 2 immunity. We conclude that clinical improvement of AD that is mediated by interleukin-4 receptor α inhibition and the subsequent suppression of type 2 inflammation is correlated with increased microbial diversity and reduced abundance of S. aureus.

  • Peripheral Sensitization and Loss of Descending Inhibition Is a Hallmark of Chronic Pruritus
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-07-02
    Esther M. Pogatzki-Zahn; Manuel P. Pereira; Alexander Cremer; Claudia Zeidler; Tim Dreyer; Claudia Riepe; Carola Wempe; Tobias Lotts; Daniel Segelcke; Matthias Ringkamp; Andreas E. Kremer; Konstantin Agelopoulos; Sonja Ständer

    Neurophysiological mechanisms leading to chronicity of pruritus are not yet fully understood and it is not known whether these mechanisms diverge between different underlying diseases of chronic pruritus (CP). This study aimed to detect such mechanisms in CP of various origins. A total of 120 patients with CP of inflammatory origin (atopic dermatitis), neuropathic origin (brachioradial pruritus), and chronic prurigo of nodular type, the latter as a model for chronic scratching, as well as 40 matched healthy controls participated in this study. Stimulation with cowhage induced a more intensive itch sensation compared with stimulation with other substances in all patient groups but not in healthy controls, arguing for sensitization of cutaneous mechano- and heat-sensitive C-fibers in CP. All patient groups showed a decreased intraepidermal nerve fiber density compared with controls. A decreased condition pain modulation effect was observed in all patient groups compared with controls, suggesting a reduced descending inhibitory system in CP. In sum, CP of different etiologies showed a mixed peripheral and central pattern of neuronal alterations, which might contribute to the chronicity of pruritus with no differences between pruritus entities. Our findings may contribute to the development of future treatment strategies targeting these pathomechanisms.

  • Data Independent Acquisition Proteomic Analysis Can Discriminate between Actinic Keratosis, Bowen’s Disease, and Cutaneous Squamous Cell Carcinoma
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-06-27
    Ali Azimi; Pengyi Yang; Marina Ali; Vicki Howard; Graham J. Mann; Kimberley L. Kaufman; Pablo Fernandez-Penas

    Actinic keratosis, Bowen’s disease and cutaneous squamous cell carcinoma (cSCC) are heterogeneous keratinocytic skin lesions. Biomarkers that can accurately stratify these lesion types are needed to support a new paradigm of personalized and precise management of skin neoplasia. In this paper, we used a data independent acquisition proteomics workflow, sequential window acquisition of all theoretical mass spectra, to analyze formalin-fixed paraffin-embedded samples of normal skin and keratinocytic skin lesions, including well-differentiated, moderately differentiated and poorly differentiated cSCC lesions. We quantified 3,574 proteins across the 93 samples studied. Differential abundance analysis identified 19, 5, and 6 protein markers exclusive to actinic keratosis, Bowen’s disease and cSCC lesions, respectively. Among cSCC lesions of various levels of tumor differentiation, 118, 230, and 17 proteins showed a potential as biomarkers of well-differentiated, moderately differentiated and poorly differentiated cSCC lesions, respectively. Bioinformatics analysis revealed that actinic keratosis and cSCC lesions were associated with decreased apoptosis, and Bowen’s disease lesions with over-representation of the DNA damage repair pathway. Differential expression of alternatively spliced FGFR2, Rho guanosine triphosphatase signaling, and RNA metabolism proteins were associated with the level of cSCC tumor differentiation. Proteome profiles also separated keratinocytic skin lesion subtypes on principal components analysis. Overall, protein markers have excellent potential to discriminate keratinocytic skin lesion subtypes and facilitate new diagnostic and therapeutic strategies.

  • Cutaneous Wound Healing in Diabetic Mice Is Improved by Topical Mineralocorticoid Receptor Blockade
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-07-03
    Van Tuan Nguyen; Nicolette Farman; Roberto Palacios-Ramirez; Maria Sbeih; Francine Behar-Cohen; Sélim Aractingi; Frederic Jaisser

    Skin ulcers resulting from impaired wound healing are a serious complication of diabetes. Unresolved inflammation, associated with the dysregulation of both the phenotype and function of macrophages, is involved in the poor healing of diabetic wounds. Here, we report that topical pharmacological inhibition of the mineralocorticoid receptor (MR) by canrenoate or MR small interfering RNA can resolve inflammation to improve delayed skin wound healing in diabetic mouse models; importantly, wounds from normal mice are unaffected. The beneficial effect of canrenoate is associated with an increased ratio of anti-inflammatory M2 macrophages to proinflammatory M1 macrophages in diabetic wounds. Furthermore, we show that MR blockade leads to downregulation of the MR target, LCN2, which may facilitate macrophage polarization toward the M2 phenotype and improve impaired angiogenesis in diabetic wounds. Indeed, diabetic LCN2-deficient mice showed improved wound healing associated with macrophage M2 polarization and angiogenesis. In addition, recombinant LCN2 protein prevented IL-4–induced macrophage switch from M1 to M2 phenotype. In conclusion, topical MR blockade accelerates skin wound healing in diabetic mice via LCN2 reduction, M2 macrophage polarization, prevention of inflammation, and induction of angiogenesis.

  • Using Implementation Science to Optimize the Uptake of Evidence-Based Medicine into Dermatology Practice
    J. Invest. Dermatol. (IF 6.290) Pub Date : 2019-12-18
    Sepideh Ashrafzadeh; Joshua P. Metlay; Niteesh K. Choudhry; Karen M. Emmons; Maryam M. Asgari

    An estimated 17-year lag exists between evidence generation and its integration into routine clinical care. The field of implementation science has emerged to close this gap by applying rigorous methods to systematically study the obstacles and facilitators of the uptake of evidence-based practices. However, implementation science has not gained wide traction in dermatology. In this narrative review, we use literature and expert input to introduce implementation science and key frameworks for implementing interventions and evaluating their uptake. We then highlight opportunities for dermatology-specific interventions at the patient-, provider-, system-, and population-levels, and advocate for the field’s expansion into dermatology.

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上海纽约大学William Glover