Dermatology
Abstract
Psoriatic arthritis (PsA) is a complex inflammatory disease that challenges diagnosis and complicates the rational selection of effective therapies. Although T cells are considered active effectors in psoriasis and PsA, the role of CD8+ T cells in pathogenesis is not well understood. We selected the humanized mouse model NSG-SGM3 transgenic strain to examine psoriasis and PsA endotypes. Injection of PBMCs and sera from patients with psoriasis and PsA generated parallel skin and joint phenotypes in the recipient mouse. The transfer of human circulating memory T cells was followed by migration and accumulation in the skin and synovia of these immunodeficient mice. Unexpectedly, immunoglobulins were required for recapitulation of the clinical phenotype of psoriasiform lesions and PsA domains (dactylitis, enthesitis, bone erosion). Human CD8+ T cells expressing T-bet, IL-32 and CXCL14 were detected by spatial transcriptomics in murine synovia and by immunofluorescence in the human PsA synovia. Importantly, depletion of human CD8+ T cells prevented skin and synovial inflammation in mice humanized with PsA peripheral blood cells. The humanized model of psoriasis and PsA represents a valid platform for accelerating the understanding of disease pathogenesis, improving the design of personalized therapies, and revealing psoriatic disease targets.
Authors
Christopher T. Ritchlin, Javier Rangel-Moreno, Delaney Martino, Brian Isett, Ananta Paine, Soumyaroop Bhattacharya, Jeffrey Fox, Ernest M. Meyer, Riyue Bao, Tullia Bruno, Francisco Tausk, Maria de la Luz Garcia-Hernandez
Abstract
Hypotrichosis is a genetic disorder which characterized by a diffuse and progressive loss of scalp and/or body hair. Nonetheless, the causative genes for several affected individuals remain elusive, and the underlying mechanisms have yet to be fully elucidated. Here, we discovered a dominant variant in ADAM17 gene caused hypotrichosis with woolly hair. Adam17 (p.D647N) knock-in mice model mimicked the hair abnormality in patients. ADAM17 (p.D647N) mutation led to hair follicle stem cells (HFSCs) exhaustion and caused abnormal hair follicles, ultimately resulting in alopecia. Mechanistic studies revealed that ADAM17 binds directly to E3 ubiquitin ligase TRIM47. ADAM17 (p.D647N) variant enhanced the association between ADAM17 and TRIM47, leading to an increase in ubiquitination and subsequent degradation of ADAM17 protein. Furthermore, reduced ADAM17 protein expression affected Notch signaling pathway, impairing the activation, proliferation, and differentiation of HFSCs during hair follicle regeneration. Overexpression of NICD rescued the reduced proliferation ability caused by Adam17 variant in primary fibroblast cells.
Authors
Xiaoxiao Wang, Chaolan Pan, Luyao Zheng, Jianbo Wang, Quan Zou, Peiyi Sun, Kaili Zhou, Anqi Zhao, Qiaoyu Cao, Wei He, Yumeng Wang, Ruhong Cheng, Zhirong Yao, Si Zhang, Hui Zhang, Ming Li
Abstract
Atopic dermatitis (AD) is an inflammatory skin condition with a childhood prevalence of up to 25%. Microbial dysbiosis is characteristic of AD, with Staphylococcus aureus the most frequent pathogen associated with disease flares and increasingly implicated in disease pathogenesis. Therapeutics to mitigate the effects of S. aureus have had limited efficacy and S. aureus–associated temporal disease flares are synonymous with AD. An alternative approach is an anti–S. aureus vaccine, tailored to AD. Experimental vaccines have highlighted the importance of T cells in conferring protective anti–S. aureus responses; however, correlates of T cell immunity against S. aureus in AD have not been identified. We identify a systemic and cutaneous immunological signature associated with S. aureus skin infection (ADS.aureus) in a pediatric AD cohort, using a combined Bayesian multinomial analysis. ADS.aureus was most highly associated with elevated cutaneous chemokines IP10 and TARC, which preferentially direct Th1 and Th2 cells to skin. Systemic CD4+ and CD8+ T cells, except for Th2 cells, were suppressed in ADS.aureus, particularly circulating Th1, memory IL-10+ T cells, and skin-homing memory Th17 cells. Systemic γδ T cell expansion in ADS.aureus was also observed. This study suggests that augmentation of protective T cell subsets is a potential therapeutic strategy in the management of S. aureus in AD.
Authors
Julianne Clowry, Daniel J. Dempsey, Tracey J. Claxton, Aisling M. Towell, Mary B. Turley, Martin Sutton, Joan A. Geoghegan, Sanja Kezic, Ivone Jakasa, Arthur White, Alan D. Irvine, Rachel M. McLoughlin
Abstract
Loss-of-Function (LoF) variants in the filaggrin (FLG) gene are the strongest known genetic risk factor for atopic dermatitis (AD), but the impact of these variants on AD outcomes is poorly understood. We comprehensively identified genetic variants through targeted region sequencing of FLG in children (n = 438) participating in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) cohort. Twenty FLG LoF variants were identified, including one novel variant and nine variants not previously associated with AD. FLG LoF variants were found in 13.6% of the cohort. Among these children, the presence of one or more FLG LoF variants was associated with moderate/severe AD (odds ratio (OR) = 2.00 (95% CI, 1.23–3.68) compared to those with mild AD. Children with FLG LoF variants had a higher SCORAD (SCORing for Atopic Dermatitis (SCORAD); P = 0.012) and higher likelihood of food allergy within the first 2.5 years of life (OR = 2.81, 1.50–5.26). LoF variants were associated with higher transepidermal Water Loss (TEWL) in both lesional (P = 0.018) and non-lesional skin (P = 0.015). Collectively, our study identifies established and novel AD-associated FLG LoF variants and associates FLG LoF with higher TEWL in lesional and non-lesional skin.
Authors
Samuel J. Virolainen, Latha Satish, Jocelyn M. Biagini, Hassan Chaib, Wan Chi Chang, Phillip J. Dexheimer, Michael R. Dixon, Katelyn A. Dunn, David Fletcher, Carmy Forney, Marissa Granitto, Matthew S. Hestand, Makenna Hurd, Kenneth Kaufman, Lucinda P. Lawson, Lisa J. Martin, Loren D.M. Peña, Kieran J. Phelan, Molly S. Shook, Matthew T. Weirauch, Gurjit K. Khurana Hershey, Leah C. Kottyan
Abstract
Central for wound healing is the formation of granulation tissue, which largely consists of collagen and whose importance stretches past wound healing, including being implicated in both fibrosis and skin aging. Cyclophilin D (CyD) is a mitochondrial protein that regulates the permeability transition pore, known for its role in apoptosis and ischemia-reperfusion. To date, the role of CyD in human wound healing and collagen generation ihas been largely unexplored. Here, we show that CyD was upregulated in normal wounds and venous ulcers, likely adaptive as CyD inhibition impaired re-epithelialization, granulation tissue formation, and wound closure in both human and pig models. Overexpression of CyD increased keratinocyte migration and fibroblast proliferation, whilst its inhibition reduced migration. Independent of wound healing, CyD inhibition in fibroblasts reduced collagen secretion and caused endoplasmic reticulum collagen accumulation, while its overexpression increased collagen secretion. This was confirmed in a Ppif knockout mouse model, which showed a reduction in skin collagen. Overall, this study revealed previously unreported roles of CyD in skin, with implications for wound healing and beyond.
Authors
Ritu Bansal, Monica Torres, Matthew Hunt, Nuoqi Wang, Margarita Chatzopoulou, Mansi Manchanda, Evan P. Taddeo, Cynthia Shu, Orian S. Shirihai, Etty Bachar-Wikstrom, Jakob D. Wikstrom
Abstract
IL-17C is an epithelial cell-derived proinflammatory cytokine whose transcriptional regulation remains unclear. Analysis of the IL17C promoter region identified TCF4 as putative regulator and siRNA knockdown of TCF4 in human keratinocytes (KCs) increased IL17C. IL-17C stimulation of KCs (along with IL-17A and TNF-α) decreased TCF4 and increased NFKBIZ and ZC3H12A expression in an IL-17RA/RE-dependent manner thus creating a feedback loop. ZC3H12A (MCPIP1/Regnase-1), a transcriptional immune-response regulator also increased following TCF4 siRNA knockdown and siRNA knockdown of ZC3H12A decreased NFKBIZ, IL1B, IL36G, CCL20, and CXCL1, revealing a proinflammatory role for ZC3H12A. Examination of lesional skin from the KC-Tie2 inflammatory dermatitis mouse model identified decreases in TCF4 protein concomitant with increases in IL-17C and Zc3h12a, that reversed following the genetic elimination of Il17c, Il17ra, and Il17re and improvement in the skin phenotype. Conversely, interference with Tcf4 in KC-Tie2 mouse skin increased Il17c and exacerbated the inflammatory skin phenotype. Together these findings identify a role for TCF4 in the negative regulation of IL-17C, which alone and with TNF-α and IL-17A, feedback to decrease TCF4 in an IL-17RA/RE-dependent manner. This loop is further amplified by IL-17C-TCF4 autocrine regulation of ZC3H12A and IL-17C regulation of NFKBIZ to promote self-sustaining skin inflammation.
Authors
Yanyun Jiang, Dennis Gruszka, Chang Zeng, William R. Swindell, Christa Gaskill, Christian Sorensen, Whitney Brown, Roopesh Singh Gangwar, Lam C. Tsoi, Joshua Webster, Sigrun Laufey Sigurdardottir, Mrinal K. Sarkar, Ranjitha Uppala, Austin Kidder, Xianying Xing, Olesya Plazyo, Enze Xing, Allison C. Billi, Emanual Maverakis, J. Michelle Kahlenberg, Johann Gudjonsson, Nicole L. Ward
Abstract
Fibroblasts are stromal cells known to regulate local immune responses important for wound healing and scar formation; however, the cellular mechanisms driving damage and scarring in cutaneous lupus erythematosus (CLE) patients remain poorly understood. Dermal fibroblasts in systemic lupus erythematosus (SLE) patients are abnormally exposed to cytokines, but the impact of inflammatory mediators on fibroblast responses in non-scarring versus scarring CLE subtypes is unclear. Here, we examined responses to cytokines in dermal fibroblasts from non-lesional skin of 22 SLE patients with CLE and 34 healthy controls. Notably, inflammatory cytokine responses were exaggerated in SLE fibroblasts compared to healthy controls. In lesional CLE biopsies, these same inflammatory profiles were reflected in single cell RNA sequencing of SFRP2+ and inflammatory fibroblast subsets, and TGF-β was identified as a critical upstream regulator for inflammatory fibroblasts in scarring discoid lupus lesions. In vitro cytokine stimulation of non-lesional fibroblasts from patients who scar from CLE identified an upregulation of collagens, particularly in response to TGF-β, whereas inflammatory pathways were more prominent in non-scarring patients. Our study revealed that SLE fibroblasts are poised to hyper-respond to inflammation, with differential responses among scarring versus non-scarring disease, providing a potential skin-specific target for mitigating damage.
Authors
Suzanne K. Shoffner-Beck, Lisa Abernathy-Close, Stephanie Lazar, Feiyang Ma, Mehrnaz Gharaee-Kermani, Amy Hurst, Craig Dobry, Deepika Pandian, Rachael Wasikowski, Amanda Victory, Kelly Arnold, Johann E. Gudjonsson, Lam C. Tsoi, J. Michelle Kahlenberg
Abstract
Dedifferentiation or phenotype switching refers to the transition from a proliferative to an invasive cellular state. We previously identified a 122-gene epigenetic gene signature that classifies primary melanomas as low- versus high-risk (denoted as Epgn1 or Epgn3). We found that the transcriptomes of the Epgn1 low-risk and Epgn3 high-risk cells are similar to the proliferative and invasive cellular states, respectively. These signatures were further validated in melanoma tumor samples. Examination of the chromatin landscape revealed differential H3K27 acetylation in the Epgn1 low-risk versus Epgn3 high-risk cell lines that corroborated with a differential super-enhancer and enhancer landscape. Melanocytic lineage genes (MITF, its targets and regulators) were associated with super-enhancers in the Epgn1 low-risk state whereas invasiveness genes were linked with Epgn3 high-risk status. We identified ITGA3 gene as marked by a super-enhancer element in the Epgn3 invasive cells. Silencing of ITGA3 enhanced invasiveness in both in vitro and in vivo systems suggesting it as a negative regulator of invasion. In conclusion, we define chromatin landscape changes associated with Epgn1/3 and phenotype switching during early steps of melanoma progression that regulate transcriptional reprogramming. This super-enhancer and enhancer-driven epigenetic regulatory mechanism resulting in major changes in the transcriptome could be important in future therapeutic targeting efforts.
Authors
Karen Mendelson, Tiphaine C. Martin, Christie B. Nguyen, Min Hsu, Jia Xu, Claudia C.V. Lang, Reinhard Dummer, Yvonne Saenger, Jane L. Messina, Vernon K. Sondak, Garrett Desman, Dan Hasson, Emily Bernstein, Ramon E. Parsons, Julide Tok Celebi
Abstract
Long noncoding RNAs (lncRNAs) regulate the expression of protein-coding genes and have been shown to play important roles in inflammatory skin diseases. However, we still have limited understanding of the functional impact of lncRNAs in skin, partly due to their tissue specificity and lower expression levels compared with protein-coding genes. We compiled a comprehensive list of 18,517 lncRNAs from different sources and studied their expression profiles in 834 RNA-Seq samples from multiple inflammatory skin conditions and cytokine-stimulated keratinocytes. Applying a balanced random forest to predict involvement in biological functions, we achieved a median AUROC of 0.79 in 10-fold cross-validation, identifying significant DNA binding domains (DBDs) for 39 lncRNAs. G18244, a skin-expressing lncRNA predicted for IL-4/IL-13 signaling in keratinocytes, was highly correlated in expression with F13A1, a protein-coding gene involved in macrophage regulation, and we further identified a significant DBD in F13A1 for G18244. Reflecting clinical implications, AC090198.1 (predicted for IL-17 pathway) and AC005332.6 (predicted for IFN-γ pathway) had significant negative correlation with the SCORAD metric for atopic dermatitis. We also utilized single-cell RNA and spatial sequencing data to validate cell type specificity. Our research demonstrates lncRNAs have important immunological roles and can help prioritize their impact on inflammatory skin diseases.
Authors
Matthew T. Patrick, Sutharzan Sreeskandarajan, Alanna Shefler, Rachael Wasikowski, Mrinal K. Sarkar, Jiahan Chen, Tingting Qin, Allison C. Billi, J. Michelle Kahlenberg, Errol Prens, Alain Hovnanian, Stephan Weidinger, James T. Elder, Chao-Chung Kuo, Johann E. Gudjonsson, Lam C. Tsoi
Abstract
Hidradenitis suppurativa (HS) is a chronic skin condition affecting approximately 1% of the US population. HS skin lesions are highly inflammatory and characterized by a large immune infiltrate. While B cells and plasma cells comprise a major component of this immune milieu the biology and contribution of these cells in HS pathogenesis is unclear. We aimed to investigate the dynamics and microenvironmental interactions of B cells within cutaneous HS lesions. Combining histological analysis, single-cell RNA-sequencing (scRNAseq), and spatial transcriptomic profiling of HS lesions we define the tissue microenvironment relative to B cell activity within this disease. Our findings identify tertiary lymphoid structures (TLS) within HS lesions and describe organized interactions between T cells, B cells, antigen presenting cells and skin stroma. We find evidence that B cells within HS TLS actively undergo maturation, including participation in germinal center reactions and class switch recombination. Moreover, skin stroma and accumulating T cells are primed to support the formation of TLS and facilitate B cell recruitment during HS. Our data definitively demonstrate the presence of TLS in lesional HS skin and point to ongoing cutaneous B cell maturation through class switch recombination and affinity maturation during disease progression in this inflamed non-lymphoid tissue.
Authors
Margaret M. Lowe, Jarish N. Cohen, Madison I. Moss, Sean Clancy, James P. Adler, Ashley E. Yates, Haley B. Naik, Rashi Yadav, Mariela Pauli, Ian Taylor, Austin McKay, Hobart Harris, Esther Kim, Scott L. Hansen, Michael D. Rosenblum, Joshua M. Moreau
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