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IL-1 inhibition in systemic sclerosis skin.

ABSTRACT: IL-1 inhibition in systemic sclerosis skin.

PROVIDER: PRJNA490744 | ENA |

REPOSITORIES: ENA

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IL-1 inhibition in systemic sclerosis skin.

Project description:IL-1 has been implicated in various fibrotic diseases. This randomized, Placebo-Controlled trial we examine the effect of il1-b inhibition on skin expression. We used microarrays to explore gene expression changes in the Rilonacept clinical trial

2019-09-12 | GSE119939 | GEO

Combined inhibition of IL-1, IL-33 and IL-36 signaling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of Systemic Sclerosis

Project description:Background: The IL-1 receptor accessory protein (IL1RAP) is an essential co-receptor required for signaling through the IL-1, IL-33 and IL-36 receptors. Here, we investigate the antifibrotic potential of the combined inhibition of these cytokines by an anti-IL1RAP antibody to provide a scientific background for clinical development in systemic sclerosis (SSc). Methods: The expression of IL1RAP-associated signaling molecules was determined by data mining of publicly available RNAseq data as well as by imaging mass cytometry (IMC). Efficacy of therapeutic dosing of anti-IL1RAP antibodies was determined in three complimentary mouse models: chronic sclerodermatous graft-versus-host-disease (cGvHD), bleomycin-induced dermal fibrosis model and topoisomerase-I (topo)-induced fibrosis. Results: SSc skin showed upregulation of IL1RAP and IL1RAP-related signaling molecules on mRNA and protein level compared to normal skin. IL-1, IL-33, and IL-36 all regulate distinct genes sets related to different pathophysiological processes in SSc. The responses of human fibroblasts and endothelial cells to IL-1, IL-33, and IL-36 were completely blocked by treatment with an anti-IL1RAP-antibody in vitro. Moreover, anti-IL1RAP antibody treatment reduced dermal and pulmonary fibrosis in cGvHD-, bleomycin- and topoisomerase-induced fibrosis. Importantly, RNAseq analyses revealed effects of IL1RAP inhibition on multiple processes related to inflammation and fibrosis that are also deregulated in human SSc skin. Conclusion: This study provides first evidence for the therapeutic benefits of targeting of IL1RAP in SSc. Our findings have high translational potential as the anti-IL1RAP antibody CAN10 has recently entered a phase 1 clinical trial.

2024-04-30 | GSE255031 | GEO

Expression data from skin biopsies in pateints with systemic sclerosis treated with anti-TGF-beta, fresolimumab

Project description:Systemic sclerosis is associated with skin fibrosis thought mediated by TGFb. This open label clinical trial examines the effect of TGFb inhibition on skin gene expression. Patients 1-9 received two doses 1 mg/kg dose of fresolimumab at baseline and 3 weeks; patients 10-19 received a single 5 mg/kg dose Patients with diffuse cutaneous systemic sclerosis within 2 years of first raynauds had skin biopsies before treatment and the 3-4 weeks, 7 weeks and 24 weeks after treatment with fresolimumab

2015-06-05 | E-GEOD-55036 | biostudies-arrayexpress

Dissecting the heterogeneity of skin gene expression patterns in systemic sclerosis.

Project description:We identified fibro-inflammatory and keratin gene expression signatures in systemic sclerosis skin.

2015-05-26 | GSE58095 | GEO

Combined inhibition of IL-1, IL-33 and IL-36 signaling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of Systemic Sclerosis

Project description:Combined inhibition of IL-1, IL-33 and IL-36 signaling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of Systemic Sclerosis

| PRJNA1073269 | ENA

Dissecting the heterogeneity of skin gene expression patterns in systemic sclerosis.

Project description:We identified fibro-inflammatory and keratin gene expression signatures in systemic sclerosis skin. Skin biopsy samples from 61 patients enrolled in the GENISOS cohort or an open label imatinib study (baseline sample) and 36 controls were examined by global gene expression studies. 5 patients were sampled at two time points (early-late). There is overlap between this data set and GSE47162.

2015-05-26 | E-GEOD-58095 | biostudies-arrayexpress

Expression data from skin biopsies in pateints with systemic sclerosis treated with anti-TGF-beta, fresolimumab

2015-06-05 | GSE55036 | GEO

Skin gene expression correlates of severity of interstitial lung disease in systemic sclerosis

Project description:We identified eighty two skin transcripts significantly correlated with the severity of interstitial lung disease (ILD) in systemic sclerosis. These genes separated patients with more sever ILD in unsupervised hierarchical clustering. Pathway analysis revealed pathways involved in extravasation and adhesion of inflammatory cells to endothelium. Skin biopsy samples from 59 patients enrolled in the GENISOS cohort or an open label imatinib study were examined by global gene expression studies.

2013-07-12 | E-GEOD-47162 | biostudies-arrayexpress

Gene expression from human keratinocytes isolated from limited systemic sclerosis (lcSSc) and diffuse systemic sclerosis (dcSSc) skin biopsy

Project description:Systemic sclerosis (SSc) is a rare but devastating disease of fibrosis impacting the dermis and multiple organ systems. The prevalence ranges from 4 to 489 cases per million individuals with ten year mortality rates reported around 18 percent. Survival is related to the extent of skin involvement, yet the precise mechanisms driving skin fibrosis in SSc remain unknown. In this study, we analyzed the shared and unique transcriptomic profiles of SSc and normal keratinocytes.

2018-03-21 | GSE81072 | GEO

IL-25 participates in keratinocyte-driven dermal matrix turnover and is reduced in Systemic Sclerosis epidermis

Project description:Aberrant deposition of extracellular matrix (ECM) resulting in dermal fibrosis is a hallmark of systemic sclerosis (SSc). Evidence suggests that dysfunctional SSc keratinocytes may contribute to fibrosis by altering dermal homeostasis. Whether interleukin-25 (IL-25), an IL-17 family member involved in epithelial/mesenchymal/immune cell interplay takes part in skin fibrosis is unknown. Here we address the role of IL-25 in SSc skin fibrosis. Compared to healthy donor (HD), in SSc and scleroderma-like disorders the epidermis expressed significantly lower levels of IL-25. In epidermal equivalents, IL-25 regulated several molecular pathways related to wound healing and ECM remodeling. Compared to control conditioned medium (CM), the CM from IL-25-primed keratinocytes enhanced the production by fibroblasts of matrix metalloproteinase-1 (MMP-1), IL-6, IL-8 (p< 0.05), but not of type-I collagen (Col-I ) nor fibronectin. However, IL- 25 significantly reduced the production of Col-I when applied directly to fibroblasts. The activation of keratinocytes by IL-25 was receptor-dependent and evident after a very short incubation time (10 min), largely mediated by IL-1, suggesting enhanced and specific release of preformed mediators. These results show that IL-25 participates to skin homeostasis and its decreased expression in SSc may contribute to skin fibrosis by favoring ECM deposition over degradation.

2022-03-31 | GSE168312 | GEO

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