Single cell analysis of psoriasis resolution following IL-23 blockade
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PROVIDER: PRJNA996725 | ENA |
REPOSITORIES: ENA
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Project description:Single cell analysis of psoriasis resolution following IL-23 blockade
| PRJNA996724 | ENA
Project description:Psoriasis vulgaris and other chronic inflammatory diseases improve markedly with therapeutic blockade of IL-23 signaling in T cells, but the genetic mechanisms of response remain poorly understood. We single-cell transcriptomically profiled CD45+ immune cells isolated from lesional psoriatic skin before and after IL-23 blockade. In clinically responsive patients, a psoriatic transcriptional signature in skin-resident memory T cells was sharply attenuated. In contrast, poorly responsive patients were distinguished by enduring T17 cell activation, a mechanism distinct from alternative cytokine signaling or downstream resistance. Spatial transcriptomic analysis suggests that successful IL-23 blockade requires dampening of > 90% of IL-17-induced signaling in lymphocyte-adjacent keratinocytes, an unexpectedly high threshold. We also detected a subset of persistent, disease-specific T17 abnormalities in responsive patients, revealing an irreversible cell identity that may necessitate ongoing IL-23 inhibition. Collectively, our data establishes a patient-level paradigm for dissecting response to immunomodulatory treatments.
| EGAS00001007373 | EGA
Project description:Durable psoriasis improvement has been reported in a subset of psoriasis patients after treatment withdrawal of biologics blocking IL-23/Type 17 T-cell (T17) autoimmune axis. However, it is not well understood if systemic blockade of the IL-23/T17 axis promotes immune tolerance in psoriasis skin. The purpose of the study was to find translational evidence that systemic IL-17A blockade promotes regulatory transcriptome modification in human psoriasis skin immune cell subsets. We analyzed human psoriasis lesional skin 6 mm punch biopsy tissues before and after systemic IL-17A blockade using the muti-genomics approach integrating immune cell-enriched scRNA-seq (n = 18), microarray (n = 61), and immunohistochemistry (n = 61) with repository normal control skin immune cell-enriched scRNA-seq (n = 10) and microarray (n = 8) data. For the T17 axis transcriptome, systemic IL-17A blockade depleted 100% of IL17A + T-cells and 95% of IL17F + T-cells in psoriasis skin. The expression of IL23A in DC subsets was also downregulated by IL-17A blockade. The expression of IL-17-driven inflammatory mediators (IL36G, S100A8, DEFB4A, and DEFB4B) in suprabasal keratinocytes was correlated with psoriasis severity and was downregulated by IL-17A blockade. For the regulatory DC transcriptome, the proportion of regulatory semimature DCs expressing regulatory DC markers of BDCA-3 (THBD) and DCIR (CLEC4A) was increased in posttreatment psoriasis lesional skin compared to pretreatment psoriasis lesional skin. In addition, IL-17A blockade induced higher expression of CD1C and CD14, which are markers of CD1c+ CD14+ dendritic cell (DC) subset that suppresses antigen-specific T-cell responses, in posttreatment regulatory semimature DCs compared to pretreatment regulatory semimature DCs. In conclusion, systemic IL-17A inhibition not only blocks the entire IL-23/T17 cell axis but also promotes regulatory gene expression in regulatory DCs in human psoriasis skin.
2023-09-04 | GSE183047 | GEO
Project description:Pyoderma Gangrenosum (PG) is a rare and extremely painful neutrophilic dermatosis associated with non-healing cutaneous ulcers affecting 3-10 individuals per million people. The etiology and molecular pathogenetic events of this disease are yet unknown. To investigate how this therapeutic regime shaped the underlying inflammatory response, we performed spatial transcriptomics on lesional biopsies from patients before and after ustekinumab treatment. Our study provides high resolution temporal insights into the inflammatory environment of PG lesional skin following treatment with IL-12/IL-23 blockade in two patients with classic and peristomal PG. This work highlights that while inhibition of representative cytokines of the Th1 and Th17 pathways shows promise as a treatment for PG patients, it does not dampen all active inflammatory pathways.
2024-08-28 | GSE274489 | GEO
Project description:Purpose: We aimed to find a potential for psoriasis and to explore the mechanism of SBM to relieve psoriasis-like skin inflammation in mice. Methods: Supplementation with smear administration of SBM in the imiquimod-induced murine model, record the weight change and psoriasis Area and Severity Index (PASI) score during the whole process. Using hematoxylin-eosin staining to obverse to skin structure. Performing single-cell RNA sequencing to explore the mechanism of SBM in influencing psoriasis-like phenotype. Immunofluorescence were conducted for verification. Results: SBM remarkably alleviated the psoriasis-like phenotype. Single-cell RNA sequencing analysis shown the expression of Il17 and Il23 was diminished in keratinocytes and T cells, accompanied by a reduction in the proportion of Th17 cells. Meanwhile, endothelial cell activation was inhibited along with the expression of Cxcl16. Conclusion: In this work, we found that natural product SBM inhibited the IL-23/Th17 axis and CXCL16-mediated endothelial activation and had a good therapeutic effect on psoriasis in mice model. This work suggests the potential therapeutic value of SBM in psoriatic patients.
2023-11-21 | GSE232568 | GEO
Project description:The success of TNF inhibitors for treatment of psoriasis and other inflammatory diseases was previously attributed to blockade of innate immunity. In a clinical trial using etanercept TNF blocking agent to treat psoriasis vulgaris, we used affymetrix gene arrays to analyze broad gene profiles in lesional skin at multiple timepoints during drug treatment (baseline, and weeks 1, 2, 4 and 12) compared to non-lesional skin. This analysis created a temporal model of TNF-dependent gene regulation that informs molecular mechanisms of TNF-mediated inflammation. We identified four gene clusters that were differentially down-modulated during etanercept treatment: the cluster down-regulated most rapidly contained mostly dendritic cell activation genes. Culturing human keratinocytes with TNF, IFNg and IL-17 generated a list of keratinocyte genes regulated by each cytokine. The IL-17 pathway genes were strongly down-modulated early, whereas IFNg pathway genes were not down-modulated until final disease resolution at week 12. Finally, we show that TNF blockade rapidly inhibits IL-12/IL-23 p40 subunit expression, and that p40 neutralization inhibits psoriatic dermal emigre-mediated Th17 polarization. We hypothesize that etanercept inhibits myeloid dendritic cell production of IL-23, a Th17 survival cytokine, resulting in rapid downregulation of IL-17 pathway genes. This data links effects of TNF blockade on the innate immune system with the adaptive immune system. Experiment Overall Design: In this study 15 patients with moderate-to-severe psoriasis were given 50mg of etanercept (Amgen) biweekly for 12 weeks. And analyzed using gene array on mRNA extracted from tissue collected at each biopsy time point (non-lesional Time: 0; lesional Time: 0, weeks 1, 2, 4, and 12). Patients were stratified as 'responders' or 'non-responders' based on whether or not they achieved histologic disease resolution by week 12 of etanercept treatment (decreased epidermal thickening, normalization of proliferation marker Ki67, and loss of differentiation marker K16).
2009-11-09 | E-GEOD-11903 | biostudies-arrayexpress
Project description:Interleukin-23 (IL-23) and IL-17 are cytokines currently being targeted in clinical trials. Although inhibition of these cytokines is effective for treating psoriasis, IL-12/23 inhibition attenuates Crohn's disease, while IL-17A or IL-17RA inhibition exacerbates disease. This dichotomy between IL-23 and IL-17 was effectively modeled in the mdr1a- /- mouse model of colitis. IL-23 inhibition attenuated disease by decreasing colonic inflammation while enhancing Treg accumulation. Exacerbation of colitis by IL-17A or IL-17RA inhibition was associated with severe weakening of the intestinal epithelial barrier, culminating in increased colonic inflammation and accelerated mortality. These data show that IL-17A acts on intestinal epithelium to promote barrier function and provides insight into mechanisms underlying exacerbation of Crohn's disease when IL-17A or IL-17RA is inhibited.
2015-08-20 | GSE72212 | GEO
Project description:IL-12/IL-23 blockade reveals patterns of asynchronous inflammation in pyoderma gangrenosum
| PRJNA1146733 | ENA
Project description:We studied psoriasis skin transcriptome modification induced by systemic IL-17A blockade with microarray analyses of total skin as part of a randomized placebo-controlled clinical trial (ClinicalTrial.gov identifier: NCT03131570)
2023-09-04 | GSE226244 | GEO
Project description:Several different immune-activated cell types with particular cytokine patterns are identified such as keratinocytes, T helper cells, cytotoxic T cells, dendritic cells, macrophages, fibroblasts, and endothelial cells. The expression of well-known pathogenic factors such as TNF-α, IL-8 (CXCL8), L-23 and IL-17 is confirmed in different inflammatory cells. Furthermore, IL-14 (TXLNA; alpha-taxilin), IL-18 and IL-32 are identified as less well-known, and putative new pathogenic factors. Prominent expression of IL-18 is found in keratinocytes, macrophages and Langerhans cells, prominent IL-32 is found in T helper and regulatory T cells, IL-14 is mainly expressed by keratinocytes, fibroblasts and macrophages. Validation of gene expression is performed by ISH of human skin samples. In a murine model of psoriasis, IL-14 and IL-18 are significantly higher expressed in psoriasis-like skin lesions than in normal skin. In an analysis of serum samples from psoriasis patients, IL-18 shows higher expression in psoriasis patients compared to controls, and serum levels in psoriasis responded to treatment with IL-17 inhibitors.
2023-08-14 | GSE221648 | GEO