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Gene expression in limited cutaneous systemic sclerosis skin

ABSTRACT: Systemic sclerosis (SSc) is an autoimmune disease characterized by clinical heterogeneity, multi-organ involvement, and complex genetic risk. Here, we report the first multi-tissue meta-analysis of ten independent SSc gene expression datasets. We identify a common immune-fibrotic expression axis across all tissues that is associated with the most severe disease phenotypes. The coexpression patterns conserved across tissues and phenotypes were used to query functional genomic networks, which allowed us to identify common and tissue-specific disease drivers. We find evidence of pro-fibrotic macrophages (MØs) in SSc end-target organs. Prominent genes in the skin functional genomic network are associated with SSc genetic risk and are modulated by immunosuppressive treatment in clinical improvers. These data suggest the interactions between T lymphocytes and MØs are a critical driver of disease and implicate MØs as central to SSc pathogenesis. In total, this study presents a mechanism for fibrosis in SSc end-target tissues, a set of putative therapeutic targets for modulating SSc, and a framework for multi-tissue functional genomic studies of complex human disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE76806 | GEO | 2017/01/01

SECONDARY ACCESSION(S): PRJNA308611

REPOSITORIES: GEO

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Gene expression in limited cutaneous SSc skin

Project description:Systemic sclerosis (SSc) is an autoimmune disease characterized by clinical heterogeneity, multi-organ involvement, and complex genetic risk. Here, we report the first multi-tissue meta-analysis of ten independent SSc gene expression datasets. We identify a common immune-fibrotic expression axis across all tissues that is associated with the most severe disease phenotypes. The coexpression patterns conserved across tissues and phenotypes were used to query functional genomic networks, which allowed us to identify common and tissue-specific disease drivers. We find evidence of pro-fibrotic macrophages (MØs) in SSc end-target organs. Prominent genes in the skin functional genomic network are associated with SSc genetic risk and are modulated by immunosuppressive treatment in clinical improvers. These data suggest the interactions between T lymphocytes and MØs are a critical driver of disease and implicate MØs as central to SSc pathogenesis. In total, this study presents a mechanism for fibrosis in SSc end-target tissues, a set of putative therapeutic targets for modulating SSc, and a framework for multi-tissue functional genomic studies of complex human disease.

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Ubiquitin Proteomics Analysis of Systemic Sclerosis Lung Fibroblasts with or without KLHL42 knockdown

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Project description:Fibrotic diseases impose a major socioeconomic challenge on modern societies with limited treatment options. Adropin, a peptide hormone encoded by the energy-homeostasis-associated (ENHO) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and in vivo experiments to characterize Adropin/ENHO as a potential regulator involved in fibroblast activation and tissue fibrosis in systemic sclerosis (SSc). We demonstrated consistent downregulation of Adropin/ENHO in SSc skin across different SSc cohorts. The prototypical profibrotic cytokine TGFβ reduced Adropin/ENHO expression in a JNK-dependent manner. Restoration of Adropin signaling by therapeutic application of bioactive Adropin34-76 peptides in turn inhibited TGFβ-induced fibroblast activation and fibrotic tissue remodeling in primary human dermal fibroblasts, three-dimensional full-thickness skin equivalents, the mouse models of bleomycin-induced pulmonary fibrosis and sclerodermatous chronic graft-versus-host-disease (sclGvHD), and precision-cut human skin slices (PCSS). Knockdown of GPR19, receptor of Adropin, abrogated the antifibrotic effects of Adropin in fibroblasts. RNA-seq demonstrated that the antifibrotic effects of Adropin34-76 were functionally linked to deactivation of GLI1 dependent profibrotic transcriptional networks, which was experimentally confirmed in vitro, in vivo and ex vivo. ChIP-seq confirmed Adropin34-76-induced changes in TGFβ/GLI1 signaling. Our study thus characterizes the TGFβ-induced downregulation of Adropin/ENHO expression as a potential pathomechanism of SSc as a prototypical systemic fibrotic disease that unleashes uncontrolled activation of profibrotic GLI1 signaling. We also provide evidence in multiple preclinical models that Adropin34-76 might offer potential for the treatment of fibrosis.

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Attenuation of Fibroblast Activation and Fibrosis by Adropin in Systemic Sclerosis (SSc)

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CIS deficiency intensifies GM-CSF signaling to polarize alternative activated macrophages

Project description:GM-CSF paradoxically possesses ability to differentiate both classically activated macrophages (MØs) with dominant proinflammatory function (M1-like MØs) and alternative activated MØs with strong immunosuppressive function (M2-like MØs). The intrinsic regulatory mechanism responsible for functional polarization of MØs under GM-CSF signalling remains elusive. Here we revealed that cytokine-inducible SH2-containing protein (CIS), induced by GM-CSF, is a key determinant in controlling MØ polarization. Compared to WT MØs, Cish-/- MØs gained characteristics of alternative activated MØs (M2 MØs), showing high expression of prototypic M2 markers Arginase 1, Tgm2 and YM-1; strong suppression of T cell proliferation; and low production of IL-12 and other proinflammatory cytokines¬¬. Differing from canonical IL-4/STAT6/IRF4 signaling axis of M2 induction, development of M2 MØ characteristics in Cish-/- MØs was associated with intensified STAT5 activation and consequent IRF8 downregulation. Attenuation of GM-CSF signalling via JAK inhibition and IRF8 rescue corrected certain functional defects in Cish-/- MØs. As CIS inhibition in NK and T cells promotes anti-tumour immunity, we showed that CIS deficiency enhanced the development of intra-tumoural M2 MØs and reduced CTL induction within tumour microenvironment with elevated GM-CSF. Overall, we conclude that CIS acts as an intrinsic rheostat to control intense GM-CSF signalling in order to maintain proinflammatory functions of MØs. Targeting CIS as a checkpoint in cancer immunotherapy should consider its role in regulating myeloid cell function.

2023-01-21 | PXD018390 | Pride

Lung tissues in systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension

Project description:Objective: Pulmonary complications in systemic sclerosis (SSc), including pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH), are the leading cause of mortality. We compared the molecular fingerprint of SSc lung tissues and matching primary lung fibroblasts to those of normal donors, and patients with idiopathic pulmonary fibrosis (IPF) and idiopathic pulmonary arterial hypertension (IPAH). Methods: Lung tissues were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, or IPAH. Microarray data was analyzed using Efficiency Analysis for determination of optimal data processing methods. Real time PCR and immunohistochemistry were used to confirm differential levels of mRNA and protein, respectively. Results: We identified a consensus of 242 and 335 genes that were differentially expressed in lungs and primary fibroblasts, respectively. Enriched function groups in SSc-PF and IPF lungs included fibrosis, insulin-like growth factor signaling and caveolin-mediated endocytosis. Functional groups shared by SSc-PAH and IPAH lungs included antigen presentation, chemokine activity, and IL-17 signaling. Conclusion: Using microarray analysis on carefully phenotyped SSc and comparator lung tissues, we demonstrated distinct molecular profiles in tissues and fibroblasts of patients with SSc-associated lung disease compared to idiopathic forms of lung disease. Unique molecular signatures were generated that are disease- (SSc) and phenotype- (PF vs PAH) specific. These signatures provide new insights into pathogenesis and potential therapeutic targets for SSc lung disease.

2013-06-21 | GSE48149 | GEO

Multi-tissue functional genomic study of systemic sclerosis

Project description:Multi-tissue functional genomic study of systemic sclerosis

| PRJNA308610 | ENA

Immune complex stimulation of human monocytes

Project description:Systemic sclerosis (SSc) is an autoimmune disease and several distinct autoantibodies have been described in SSc patients, many correlating with specific clinical presentation. Numerous studies have documented the presence of immune complexes (IC) in sera, lungs and BAL of SSc patients, potentially implicating them in the pathogenesis. Monocyte/macrophage activation also have been observed in fibrotic SSc skin and lung tissue. While the upstream activators remain unknown, it is plausible that IC are amongst the key triggers in activating monocytes and sustaining the chronic inflammation and fibrosis in SSc tissue. To test this hypothesis and find the specific downstream genes regulated by IC, we compare the gene expressions of the monocytes stimulated by control medium, LPS and IC using RNA seq. OPN was one of these IC regulated genes. Our paper further suggested that circulating OPN levels serve as a systemic proxy for IC driven profibrotic macrophage activity, highlighting its potential as a promising biomarker in SSc-ILD.

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