The molecular mechanisms that underlie the detrimental effects of particulate matter (PM) on skin barrier function are poorly understood. In this study, the effects of PM2.5 on filaggrin (FLG) and skin barrier function were investigated in vitro and in vivo. The levels of FLG degradation products including pyrrolidone carboxylic acid, urocanic acid (UCA), and cis/trans UCA were significantly decreased in skin tape stripping samples of study subjects when they moved from Denver, an area with low PM2.5, to Seoul, an area with high PM2.5 count. Experimentally, PM2.5 collected in Seoul inhibited FLG, loricrin, keratin-1, desmocollin-1, and corneodesmosin, but did not modulate involucrin or claudin-1 in keratinocyte cultures. Moreover, FLG protein expression was inhibited in human skin equivalents and murine skin treated with PM2.5. We demonstrate that this process was mediated by PM2.5-induced TNF-alpha and was aryl hydrocarbon receptor-dependent. PM2.5 exposure compromised skin barrier function, resulting in increased transepidermal water loss and enhanced the penetration of FITC-dextran in organotypic and mouse skin. PM2.5-induced TNF-alpha causes FLG deficiency in the skin and subsequently induces skin barrier dysfunction. Compromised skin barrier due to PM2.5 exposure may contribute to the development and the exacerbation of allergic diseases such as AD.
Byung Eui Kim, Jihyun Kim, Elena Goleva, Evgeny Berdyshev, Jinyoung Lee, Kathryn A. Vang, Un Ha Lee, SongYi Han, Susan Leung, Clifton F. Hall, Na-Rae Kim, Irina Bronova, Eu Jin Lee, Hye-Ran Yang, Donald Y.M. Leung, Kangmo Ahn
BACKGROUND Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable disease that causes severe mucocutaneous fragility due to mutations in COL7A1 (encoding type VII collagen [C7]). In this phase I/IIa trial, we evaluated the safety and possible clinical efficacy of intravenous infusion of allogeneic human umbilical cord blood–derived mesenchymal stem cells (hUCB-MSCs) in patients with RDEB.METHODS Four adult and two pediatric patients with RDEB were treated with 3 intravenous injections of hUCB-MSCs (1 × 106 to 3 × 106 cells/kg) every 2 weeks and followed up for 8–24 months after treatment. The primary endpoint was safety. Secondary endpoints related to efficacy included clinical parameters, such as disease severity score, wound assessment, itch and pain score, and quality of life. C7 expression levels and inflammatory infiltrates in the skin, as well as serum levels of inflammatory markers and neuropeptides, were also assessed.RESULTS Intravenous hUCB-MSC infusions were well tolerated, without serious adverse events. Improvements in the Birmingham Epidermolysis Bullosa Severity Score, body surface area involvement, blister counts, pain, pruritus, and quality of life were observed with maximal effects at 56–112 days after treatment. hUCB-MSC administration induced M2 macrophage polarization and reduced mast cell infiltration in RDEB skin. Serum levels of substance P were decreased after therapy. Increased C7 expression was observed at the dermoepidermal junction in 1 of 6 patients at day 56.CONCLUSION To the best of our knowledge, this is the first clinical trial of systemic administration of allogeneic hUCB-MSCs in patients with RDEB, demonstrating safety and transient clinical benefits.TRIAL REGISTRATION ClinicalTrials.gov NCT04520022.FUNDING This work was supported by Daewoong Pharmaceutical Co. Ltd. and Kangstem Biotech Co. Ltd.
Sang Eun Lee, Seung-Ju Lee, Song-Ee Kim, Kinam Kim, Boyoung Cho, Kyounghwan Roh, Soo-Chan Kim
Mottled skin pigmentation and solar lentigines from chronic photodamage with aging involves complex interactions between keratinocytes and melanocytes. However, the precise signaling mechanisms that could serve as therapeutic targets are unclear. Herein, we report that expression of nuclear factor erythroid 2-related factor 2 (NRF2), which regulates reduction–oxidation reactions, is altered in solar lentigines and photodamaged skin. Moreover, mottled skin pigmentation in humans could be treated with topical application of the NRF2 inducer sulforaphane (SF). Similarly, ultraviolet (UV) light-induced pigmentation of wildtype mouse ear skin could be treated or prevented with SF treatment. Conversely, SF treatment was unable to reduce UV-induced ear skin pigmentation in mice deficient in NRF2 or in mice with keratinocyte-specific conditional deletion of IL-6Rα. Taken together, NRF2 and IL-6Rα signaling are involved in the pathogenesis of UV-induced skin pigmentation and specific enhancement of NRF2-signaling could represent a potential therapeutic target.
Michelle L. Kerns, Robert J. Miller, Momina Mazhar, Angel S. Byrd, Nathan K. Archer, Bret L. Pinsker, Lance S. Lew, Carly A. Dillen, Ruizhi Wang, Lloyd S. Miller, Anna L. Chien, Sewon Kang
Hidradenitis Suppurativa (HS) is a chronic skin disorder of unknown etiology that manifests as recurrent, painful lesions. Cutaneous dysbiosis and unresolved inflammation are hallmarks of active HS, but their origin and interplay remain unclear. Our metabolomic profiling of HS skin revealed an abnormal induction of the kynurenine pathway (KP) of tryptophan catabolism in dermal fibroblasts correlating with the release of KP-inducing cytokines by inflammatory cell infiltrates. Notably, over-activation of the KP in lesional skin was associated with local and systemic depletion in tryptophan. Yet the skin microbiota normally degrades host tryptophan into indoles regulating tissue inflammation via engagement of the Aryl Hydrocarbon Receptor (AHR). In HS skin lesions, we detected contextual defects in AHR activation coinciding with impaired production of bacteria-derived AHR agonists and decreased incidence of AHR ligand-producing bacteria in the resident flora. Dysregulation of tryptophan catabolism at the skin-microbiota interface thus provides a mechanism linking the immunological and microbiological features of HS lesions. In addition to revealing metabolic alterations in HS patients, our study suggests that correcting AHR signaling would help restore immune homeostasis in HS skin.
Laure Guenin-Macé, Jean-David Morel, Jean-Marc Doisne, Angèle Schiavo, Lysiane Boulet, Véronique Mayau, Pedro Goncalves, Sabine Duchatelet, Alain Hovnanian, Vincent Bondet, Darragh Duffy, Marie-Noëlle Ungeheuer, Maïa Delage, Aude Nassif, James P. Di Santo, Caroline Demangel
Hidradenitis Suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by chronic abscess formation and development of multiple draining sinus tracts in the groin, axillae, and perineum. Utilizing proteomic and transcriptomic approaches, we characterized the inflammatory responses in HS in depth, revealing immune responses centered around IFN-γ, IL-36, and TNF, with lesser contribution from IL-17A. We further identified B cells and plasma cells, with associated increases in immunoglobulin production and complement activation, as pivotal players in HS pathogenesis, with BTK and SYK pathway activation as a central signal transduction networks in HS. These data provide preclinical evidence to accelerate the path towards clinical trials targeting BTK and SYK signaling in moderate to severe HS.
Johann E. Gudjonsson, Lam C. Tsoi, Feiyang Ma, Allison C. Billi, Kelsey R. van Straalen, Allard R.J.V. Vossen, H.H. Zee, Paul W. Harms, Rachael Wasikowski, Christine M. Yee, Syed Monem Rizvi, Xianying Xing, Enze Xing, Olesya Plazyo, Chang Zeng, Matthew T. Patrick, Margaret M. Lowe, Richard E. Burney, Jeffrey H. Kozlow, Jill R. Cherry-Bukowiec, Yanyun Jiang, Joseph Kirma, Stephan Weidinger, Kelly C. Cushing, Michael D. Rosenblum, Celine C. Berthier, Amanda S. MacLeod, John J. Voorhees, Fei Wen, J. Michelle Kahlenberg, Emanual Maverakis, Robert L. Modlin, Errol P. Prens
Hidradenitis suppurativa (HS) is a highly prevalent and morbid inflammatory skin disease with limited treatment options. The major cell types and inflammatory pathways in skin of HS patients are poorly understood. In addition, it is currently unknown which patients will respond to TNFα blockade. Herein, we comprehensively elucidate and functionally define the immune cell infiltrate and major inflammatory pathways in HS skin, before and after anti-TNFα therapy. We discovered that clinically and histologically healthy appearing skin (i.e., nonlesional skin) is dysfunctional in HS patients with a relative loss of immune regulatory pathways. At the cellular level, HS skin lesions were characterized by quantitative and qualitative dysfunction of type 2 dendritic cells (cDC2s), relatively reduced regulatory T cells (Tregs), an influx of memory B cells and a plasma cell/plasmablast infiltrate predominantly in end-stage fibrotic skin. At the molecular level, there was a relative bias towards the IL-1 pathway and type 1 T cell responses when compared to both healthy skin and skin from psoriasis patients. Anti-TNFα therapy significantly attenuated B cell activation with minimal effect on other inflammatory pathways. Finally, we identified an immune activation signature in skin prior to anti-TNFα treatment that correlated with subsequent lack of response to this modality. Taken together, our results reveal the fundamental immunopathogenesis of HS and provide a molecular foundation for future studies focused on stratifying patients based on likelihood of clinical response to TNFα blockade.
Margaret M. Lowe, Haley B. Naik, Sean Clancy, Mariela Pauli, Kathleen M. Smith, Yingtao Bi, Robert Dunstan, Johann Gudjonsson, Maia Paul, Hobart W. Harris, Esther A. Kim, Uk Sok Shin, Richard Ahn, Wilson Liao, Scott L. Hansen, Michael Rosenblum
Neurofibromatosis type 1 (NF1) is a rare genetic disorder, characterized by the development of benign and malignant nerve tumors. Although all individuals with NF1 harbor genetic alterations in the same gene, the clinical manifestations of NF1 are extremely heterogeneous even among individuals who carry identical genetic defects. In order to deepen the understanding of phenotypic manifestations in NF1, we comprehensively characterized the prevalence of 18 phenotypic traits in 2051 adults with NF1 from the Children’s Tumor Foundation’s NF1 registry. We further investigated the coassociation of traits and found positive correlations between spinal neurofibromas and pain, spinal neurofibromas and scoliosis, spinal neurofibromas and optic gliomas, and optic gliomas and sphenoid wing dysplasia. Furthermore, with increasing numbers of cutaneous neurofibromas, the odds ratio of malignant peripheral nerve sheath tumor increased. Phenotypic clustering revealed 6 phenotypic patient cluster subtypes: mild, freckling predominant, neurofibroma predominant, skeletal predominant, late-onset neural severe, and early-onset neural severe, highlighting potential phenotypic subtypes within NF1. Together, our results support potential shared molecular pathogenesis for certain clinical manifestations and illustrate the utility of disease registries for understanding rare diseases.
Mika M. Tabata, Shufeng Li, Pamela Knight, Annette Bakker, Kavita Y. Sarin
Scleroderma is a devastating fibrotic autoimmune disease. Current treatments are partly effective in preventing disease progression but do not remove fibrotic tissue. Here, we evaluated whether scleroderma fibroblasts take advantage of the “don’t-eat-me-signal” CD47 and whether blocking CD47 enables the body’s immune system to get rid of diseased fibroblasts. To test this approach, we used a Jun-inducible scleroderma model. We first demonstrated in patient samples that scleroderma upregulated transcription factor JUN and increased promoter accessibilities of both JUN and CD47. Next, we established our scleroderma model, demonstrating that Jun mediated skin fibrosis through the hedgehog-dependent expansion of CD26+Sca1– fibroblasts in mice. In a niche-independent adaptive transfer model, JUN steered graft survival and conferred increased self-renewal to fibroblasts. In vivo, JUN enhanced the expression of CD47, and inhibiting CD47 eliminated an ectopic fibroblast graft and increased in vitro phagocytosis. In the syngeneic mouse, depleting macrophages ameliorated skin fibrosis. Therapeutically, combined CD47 and IL-6 blockade reversed skin fibrosis in mice and led to the rapid elimination of ectopically transplanted scleroderma cells. Altogether, our study demonstrates the efficiency of combining different immunotherapies in treating scleroderma and provides a rationale for combining CD47 and IL-6 inhibition in clinical trials.
Tristan Lerbs, Lu Cui, Megan E. King, Tim Chai, Claire Muscat, Lorinda Chung, Ryanne Brown, Kerri Rieger, Tyler Shibata, Gerlinde Wernig
Systemic sclerosis (SSc) is a heterogeneous autoimmune disorder that results in skin fibrosis, autoantibody production and internal organ dysfunction. We previously identified four ‘intrinsic’ subsets of SSc based upon skin gene expression that are found across organ systems. Gene expression regulators that underlie the SSc intrinsic subsets, or are associated with clinical covariates, have not been systematically characterized. Here we present a computational framework to calculate the activity scores of gene expression regulators and identify their associations with SSc clinical outcomes. We find regulator activity scores can reproduce the intrinsic molecular subsets with distinct sets of regulators identified for inflammatory, fibroproliferative and normal-like samples. Regulators most highly correlated with modified Rodnan skin score (MRSS) also varied by intrinsic subset. We identify a subgroup of fibroproliferative/inflammatory SSc patients with more severe pathophenotypes. We further identify a subgroup of SSc patients that had higher MRSS and increased likelihood of interstitial lung disease. Using an independent cohort, we show this group was most likely to show forced vital capacity decline over a period of 36 – 54 months. Our results demonstrate an association between the activation of regulators, gene expression subsets and clinical variables that can identify SSc patients with more severe disease.
Yue Wang, Jennifer M. Franks, Monica Yang, Diana M. Toledo, Tammara A. Wood, Monique Hinchcliff, Michael L. Whitfield
Skin lesions in dermatomyositis (DM) patients are common, frequently refractory, and have prognostic significance. Histologically, DM lesions appear like cutaneous lupus erythematosus (CLE) lesions and frequently cannot be differentiated. We thus undertook to examine the transcriptional profile of DM biopsies and compared them to CLE lesions in order to identify unique features. Type I interferon (IFN) signaling, including upregulation of IFN kappa, was a common pathway in both DM and CLE, but CLE also exhibited other inflammatory pathways. Importantly, DM lesions could be distinguished from CLE by a 5-gene biomarker panel that included an upregulation of IL18. Using single-cell RNA-sequencing, we further identified keratinocytes as the main source of increased IL-18 in DM skin. The novel molecular signature identified in this study has significant clinical implications for differentiating DM from CLE lesions, and we have highlighted the potential role for IL-18 in the pathophysiology of DM skin disease.
Lam Tsoi, Mehrnaz Gharaee-Kermani, Celine C. Berthier, Tori Nault, Grace Hile, Shannon N. Estadt, Matthew T. Patrick, Rachael Wasikowski, Allison C. Billi, Lori Lowe, Tamra J. Reed, Johann Gudjonsson, J. Michelle Kahlenberg
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