Dermatology
Abstract
Pansclerotic morphea (PSM) is a rare, devastating disease characterized by extensive soft tissue fibrosis, secondary contractions, and significant morbidity. PSM pathogenesis is unknown, and aggressive immunosuppressive treatments rarely slow disease progression. We aimed to characterize molecular mechanisms driving PSM and identify therapeutically targetable pathways by performing single-cell and spatial RNA-sequencing on lesional and non-lesional skin biopsies of a PSM patient 12-months apart and 6 healthy controls. We then validated using immunostaining and in vitro approaches.Fibrotic skin was characterized by prominent type-II IFN response, accompanied by infiltrating myeloid, B-cells, and T-cells, which were the main IFN-γ source. We identified unique CXCL9+ fibroblasts enriched in PSM, characterized by increased chemokine expression, including CXCL9, CXCL10, and CCL2. CXCL9+ fibroblasts were related to profibrotic COL8A1+ myofibroblasts, which had enriched TGF-β response. In vitro, TGF-β and IFN-γ synergistically increased CXCL9 and CXCL10 expression, contributing to the perpetuation of IFN-γ responses. Further, cell-cell interaction analyses revealed cDC2B dendritic cells as a key communication hub between CXCL9+ fibroblasts and COL8A1+ myofibroblasts. These results define PSM as an inflammation-driven condition centered on type-II IFN responses. This work identified key pathogenic circuits between T-cells, cDC2Bs, and myofibroblasts, and suggests JAK1/2 inhibition is a potential therapeutic option in PSM.
Authors
Enze Xing, Feiyang Ma, Rachael Wasikowski, Allison C. Billi, Mehrnaz Gharaee-Kermani, Jennifer Fox, Craig Dobry, Amanda Victory, Mrinal Sarkar, Xianying Xing, Olesya Plazyo, Henry W. Chen, Grant C. Barber, Heidi Jacobe, Pei-Suen Tsou, Robert L. Modlin, John Varga, J. Michelle Kahlenberg, Lam C. Tsoi, Johann E. Gudjonsson, Dinesh Khanna
Abstract
Cutaneous T cell lymphoma (CTCL) is a disfiguring and incurable disease characterized by skin-homing malignant T cells surrounded by immune cells that promote CTCL growth through an immunosuppressive tumor microenvironment (TME). Preliminary data from our phase I clinical trial of anti–programmed cell death ligand 1 (anti–PD-L1) combined with lenalidomide in patients with relapsed/refractory CTCL demonstrated promising clinical efficacy. In the current study, we analyzed the CTCL TME, which revealed a predominant PD-1+ M2-like tumor-associated macrophage (TAM) subtype with upregulated NF-κB and JAK/STAT signaling pathways and an aberrant cytokine and chemokine profile. Our in vitro studies investigated the effects of anti–PD-L1 and lenalidomide on PD-1+ M2-like TAMs. The combinatorial treatment synergistically induced functional transformation of PD-1+ M2-like TAMs toward a proinflammatory M1-like phenotype that gained phagocytic activity upon NF-κB and JAK/STAT inhibition, altered their migration through chemokine receptor alterations, and stimulated effector T cell proliferation. Lenalidomide was more effective than anti–PD-L1 in downregulation of the immunosuppressive IL-10, leading to decreased expression of both PD-1 and PD-L1. Overall, PD-1+ M2-like TAMs play an immunosuppressive role in CTCL. Anti–PD-L1 combined with lenalidomide provides a therapeutic strategy to enhance antitumor immunity by targeting PD-1+ M2-like TAMs in the CTCL TME.
Authors
Zhen Han, Xiwei Wu, Hanjun Qin, Yate-Ching Yuan, Daniel Schmolze, Chingyu Su, Jasmine Zain, Lilach Moyal, Emmilia Hodak, James F. Sanchez, Peter P. Lee, Mingye Feng, Steven T. Rosen, Christiane Querfeld
Abstract
Multi-organ fibrosis in systemic sclerosis (SSc) accounts for substantial mortality and lacks effective therapies. Lying at the crossroad of transforming growth factor-β (TGF-β) and toll-like receptor (TLR) signaling, TGF-β-activated kinase 1 (TAK1) might have a pathogenic role in SSc. We therefore sought to evaluate the TAK1 signaling axis in patients with SSc, and investigate pharmacological TAK1 blockade using a novel drug-like selective TAK1 inhibitor, HS-276. Inhibiting TAK1 abrogated TGF-β1 stimulation of collagen synthesis and myofibroblasts differentiation in healthy skin fibroblasts, and ameliorated constitutive activation of SSc skin fibroblasts. Moreover, treatment with HS-276 prevented dermal and pulmonary fibrosis and reduced the expression of profibrotic mediators in bleomycin-treated mice. Importantly, initiating HS-276 treatment even after fibrosis was already established prevented its progression in affected organs. Together, these findings implicate TAK1 in the pathogenesis of SSc, and identify targeted TAK1 inhibition using a small molecule as a potential strategy for the treatment of SSc and other fibrotic diseases.
Authors
Swarna Bale, Priyanka Verma, Bharath Yalavarthi, Scott A. Scarneo, Philip F. Hughes, M. Asif Amin, Pei-Suen Tsou, Dinesh Khanna, Timothy A.J. Haystead, Swati Bhattacharyya, John Varga
Abstract
Keloid is considered as a fibro-proliferative disease characterized by chronic inflammation that is induced following skin injury. Deciphering the underlying mechanism of keloid formation is essential for improving treatment outcomes. Here, we found that more macrophages were activated towards M2 subtype in keloid dermis when compared to normal dermis. Western Blot revealed that the level of phosphorylated STAT6, a known inducer of M2 polarization, was higher in keloid fibroblasts as opposed to fibroblasts from normal dermis. Moreover, keloid fibrosis was shown to be positively correlated with the level of phosphorylated STAT6. Further, we identified downregulation of IL13RA2, a ‘decoy’ receptor of IL13, in keloid fibroblasts compared to fibroblasts from normal dermis. Ectopic expression of IL13RA2 in keloid fibroblasts resulted in inhibition of STAT6 phosphorylation, cell proliferation, migration, invasion, extracellular matrix secretion and myofibroblast marker expression, as well as an increase in apoptosis. Consistently, knockdown of IL13RA2 in normal fibroblasts induced a ‘keloidal’ status. Furthermore, both in vitro application and intra-tumoral injection of pSTAT6 inhibitor AS1517499 in a PDX keloid-implantation mouse model, resulted in proliferation inhibition, tissue necrosis, apoptosis and myofibroblast marker reduction. Collectively, this study elucidates the key role of IL13RA2 in keloid pathology and inspire further translational research of keloid treatment concerning JAK/STAT6 inhibition.
Authors
Hua Chao, Lisheng Zheng, Pojui Hsu, Jinyun He, Ridong Wu, Shuqia Xu, Ruixi Zeng, Yuan Zhou, Huisi Ma, Haibo Liu, Qing Tang
Abstract
BACKGROUND Adverse drug reactions are unpredictable immunologic events presenting frequent challenges to clinical management. Systemically administered cholecalciferol (vitamin D3) has immunomodulatory properties. In this randomized, double-blinded, placebo-controlled interventional trial of healthy human adults, we investigated the clinical and molecular immunomodulatory effects of a single high dose of oral vitamin D3 on an experimentally induced chemical rash.METHODS Skin inflammation was induced with topical nitrogen mustard (NM) in 28 participants. Participant-specific inflammatory responses to NM alone were characterized using clinical measures, serum studies, and skin tissue analysis over the next week. All participants underwent repeat NM exposure to the opposite arm and then received placebo or 200,000 IU cholecalciferol intervention. The complete rash reaction was followed by multi-omic analysis, clinical measures, and serum studies over 6 weeks.RESULTS Cholecalciferol mitigated acute inflammation in all participants and achieved 6 weeks of durable responses. Integrative analysis of skin and blood identified an unexpected divergence in response severity to NM, corroborated by systemic neutrophilia and significant histopathologic and clinical differences. Multi-omic and pathway analyses revealed a 3-biomarker signature (CCL20, CCL2, CXCL8) unique to exaggerated responders that is suppressed by cholecalciferol and implicates IL-17 signaling involvement.CONCLUSION High-dose systemic cholecalciferol may be an effective treatment for severe reactions to topical chemotherapy. Our findings have broad implications for cholecalciferol as an antiinflammatory intervention against the development of exaggerated immune responses.TRIAL REGISTRATION clinicaltrials.gov (NCT02968446).FUNDING NIH and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; grants U01AR064144, U01AR071168, P30 AR075049, U54 AR079795, and P30 AR039750 (CWRU)).
Authors
Madison K. Ernst, Spencer T. Evans, Jose-Marc Techner, Robert M. Rothbaum, Luisa F. Christensen, Ummiye Venus Onay, Dauren Biyashev, Michael M. Demczuk, Cuong V. Nguyen, Kord S. Honda, Thomas S. McCormick, Lam C. Tsoi, Johann E. Gudjonsson, Kevin D. Cooper, Kurt Q. Lu
Abstract
Rosacea is a common chronic inflammatory skin disease with a fluctuating course of excessive inflammation and apparent neovascularization. Microbial dysbiosis with high density of B. oleronius and increased activity of kallikrein 5, which cleaves cathelicidin antimicrobial peptide, are key pathogenic triggers in rosacea. However, how these events are linked to the disease remains unknown. Here, we show that type I interferons produced by plasmacytoid dendritic cells represent the pivotal link between dysbiosis, the aberrant immune response, and neovascularization. Compared to other commensal bacteria, B. oleronius is highly susceptible and preferentially killed by cathelicidin antimicrobial peptides leading to enhanced generation of complexes with bacterial DNA. These bacterial DNA-complexes but not DNA-complexes derived from host cells are required for cathelicidin-induced activation of plasmacytoid dendritic cells and type I interferon production. Moreover, kallikrein 5 cleaves cathelicidin into peptides with heightened DNA-binding and type I interferon-inducing capacities. In turn, excessive type I interferon expression drives neoangiogenesis via IL22 induction and upregulation of the IL22 receptor on endothelial cells. These findings unravel a novel pathomechanism, which directly links hallmarks of rosacea to the killing of dysbiotic commensal bacteria with induction of a pathogenic type I interferon-driven and IL22-mediated angiogenesis.
Authors
Alessio A. Mylonas, Heike C. Hawerkamp, Yichen Wang, Jiaqi Chen, Francesco Messina, Olivier Demaria, Stephan Meller, Bernhard Homey, Jeremy Di Domizio, Lucia Mazzolai, Alain Hovnanian, Michel Gilliet, Curdin Conrad
Abstract
Ocular surface diseases, including conjunctivitis, are recognized as a common comorbidity in atopic dermatitis (AD) and also occur at an increased frequency in AD patients treated with biologics targeting interleukin-4 receptor alpha (IL-4Rα) or IL-13. However, the inflammatory mechanisms underlying this pathology are unknown. Here, we developed a novel mouse model of skin inflammation-evoked conjunctivitis and showed that it is dependent on CD4+ T cells and basophils. Blockade of IL-4Rα partially attenuated conjunctivitis development, downregulated basophil activation and led to a reduction in expression of genes related to type 2 cytokine responses. Together, these data suggest that an IL-4Rα-basophil axis plays a role in the development of murine allergic conjunctivitis. Interestingly, we found a significant augmentation of a number of genes that encode tear proteins and enzymes in anti-IL-4Rα-treated mice, which may underlie the partial efficacy in this model and may represent candidate mediators of the increased frequency of conjunctivitis following dupilumab in AD patients.
Authors
Hongwei Han, Sheila Cummings, Kai-Ting C. Shade, Jennifer Johnson, George Qian, Joseph Gans, Srinivas Shankara, Javier M. Escobedo, Erik Zarazinski, Renee Bodinizzo, Dinesh S. Bangari, Paul Bryce, Alexandra Hicks
Abstract
Human papillomaviruses (HPVs), are DNA viruses, including ~450 types, classified into five genera (α-, β-, γ-, µ-, and 𝜈-HPV). The γ- and β-HPVs are present in low-copy numbers in healthy individuals, however, in patients with an inborn error of immunity, certain species of β-HPVs can cause epidermodysplasia verruciformis (EV), manifesting as recalcitrant cutaneous warts and skin cancer. EV presents as either “typical” or “atypical”. Manifestations in typical EV are limited to the skin and are caused by abnormal keratinocyte-intrinsic immunity to β-HPVs due to pathogenic sequence variants in TMC6, TMC8, or CIB1. We applied a transcriptome-based computational pipeline, VirPy, on RNA extracted from normal-appearing skin and wart samples of patients with typical EV, to explore the viral and human genetic determinants. In 26 patients, nine distinct biallelic mutations in TMC6 (5), TMC8 (1), and CIB1 (3), seven being previously unreported, were detected. Additionally, 20 different HPV species, including three α-, 16 β-, and one γ-HPVs, were detected, eight of which are being reported for the first time in EV patients (β-HPV-37, -47, -80, -151, -159, α-HPV-2, -57, and γ-HPV-128). This study expands the TMC6, TMC8, and CIB1 sequence variant spectrum and implicates new HPV subtypes in the pathogenesis of typical EV.
Authors
Amir Hossein Saeidian, Leila Youssefian, Mahtab Naji, Hamidreza Mahmoudi, Samantha M. Barnada, Charles Y. Huang, Karim Naghipoor, Amir Hozhabrpour, Jason S. Park, Flavia Manzo Margiotta, Fatemeh Vahidnezhad, Zahra Saffarian, Kambiz Kamyab-Hesari, Mohammad Tolouei, Niloofar Faraji, Seyyede Zeinab Azimi, Ghazal Namdari, Parvin Mansouri, Jean-Laurent Casanova, Vivien Béziat, Emmanuelle Jouanguy, Jouni Uitto, Hassan Vahidnezhad
Abstract
Rosacea is a chronic skin disorder characterized by abnormal neurovascular and inflammatory conditions on the central face. Despite increasing evidence suggests that rosacea is associated with metabolic disorders, the role of metabolism in rosacea pathogenesis remains unknown. Here, via targeted metabolomics approach, we characterized significantly altered metabolic signatures in rosacea patients, especially for amino acid-related metabolic pathways. Among these, glutamic acid and aspartic acid are highlighted and positively correlated with the disease severity in rosacea patients. We further demonstrated that glutamic acid and aspartic acid can facilitate the development of erythema and telangiectasia, typical features of rosacea, in the skin of mice. Mechanistically, glutamic acid and aspartic acid stimulate the production of vasodilation-related neuropeptides from peripheral neuron and keratinocytes, and induce the release of nitric oxide from endothelial cells and keratinocytes. Interestingly, we provided evidence showing that doxycycline can improve the symptoms of rosacea patients possibly by targeting amino acid metabolic pathway. These findings reveal that abnormal amino acid metabolism promotes neurovascular reactivity in rosacea, and raise the possibility of targeting dysregulated metabolism as a promising strategy for clinical treatment.
Authors
Tangxiele Liu, Wenqin Xiao, Mengting Chen, Rui Mao, San Xu, Qinqin Peng, Zhixiang Zhao, Qian Wang, Hongfu Xie, Zhili Deng, Ji Li
Abstract
Malignant melanoma is a major public health issue displaying frequent resistance to targeted therapy and immunotherapy. A major challenge is to better understand how melanoma cells evade immune elimination and how tumor growth and metastasis is facilitated by tumor microenvironment. Here, we show that expression of the cytokine TSLP by epidermal keratinocytes is induced by cutaneous melanoma in both mice and humans. Using genetically engineered models of melanoma and tumor cell grafting combined with TSLP knockout or overexpression, we defined a crosstalk between melanoma cells, keratinocytes and immune cells in establishing a tumor promoting microenvironment. Keratinocyte-derived TSLP is induced by signal(s) derived from melanoma cells and subsequently acts via immune cells to promote melanoma progression and metastasis. Furthermore, we show that TSLP signals through TSLPR-expressing dendritic cells to play an unrecognized role in promoting GATA3+ Tregs expressing a gene signature including ST2, CCR8, ICOS, PD-1, CTLA-4 and OX40 and exhibiting a potent suppressive activity on CD8+ T cell proliferation and IFNγ production. An analogous population of GATA3-expressing Tregs was also identified in human melanoma tumors. Together, our study provides novel insights into the role of TSLP in programming a pro-tumoral immune microenvironment in cutaneous melanoma.
Authors
Wenjin Yao, Beatriz German, Dounia Chraa, Antoine Braud, Cecile Hugel, Pierre Meyer, Guillaume Davidson, Patrick Laurette, Gabrielle Mengus, Eric Flatter, Pierre Marschall, Justine Segaud, Marine Guivarch, Pierre Hener, Marie-Christine Birling, Dan Lipsker, Irwin Davidson, Mei Li
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