A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis

Abstract

BackgroundSystemic sclerosis (SSc) is a multi-organ autoimmune disease characterized by skin fibrosis. Internal organ involvement is heterogeneous. It is unknown whether disease mechanisms are common across all involved affected tissues or if each manifestation has a distinct underlying pathology.MethodsWe used consensus clustering to compare gene expression profiles of biopsies from four SSc-affected tissues (skin, lung, esophagus, and peripheral blood) from patients with SSc, and the related conditions pulmonary fibrosis (PF) and pulmonary arterial hypertension, and derived a consensus disease-associate signature across all tissues. We used this signature to query tissue-specific functional genomic networks. We performed novel network analyses to contrast the skin and lung microenvironments and to assess the functional role of the inflammatory and fibrotic genes in each organ. Lastly, we tested the expression of macrophage activation state-associated gene sets for enrichment in skin and lung using a Wilcoxon rank sum test.ResultsWe identified a common pathogenic gene expression signature—an immune–fibrotic axis—indicative of pro-fibrotic macrophages (MØs) in multiple tissues (skin, lung, esophagus, and peripheral blood mononuclear cells) affected by SSc. While the co-expression of these genes is common to all tissues, the functional consequences of this upregulation differ by organ. We used this disease-associated signature to query tissue-specific functional genomic networks to identify common and tissue-specific pathologies of SSc and related conditions. In contrast to skin, in the lung-specific functional network we identify a distinct lung-resident MØ signature associated with lipid stimulation and alternative activation. In keeping with our network results, we find distinct MØ alternative activation transcriptional programs in SSc-associated PF lung and in the skin of patients with an “inflammatory” SSc gene expression signature.ConclusionsOur results suggest that the innate immune system is central to SSc disease processes but that subtle distinctions exist between tissues. Our approach provides a framework for examining molecular signatures of disease in fibrosis and autoimmune diseases and for leveraging publicly available data to understand common and tissue-specific disease processes in complex human diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0417-1) contains supplementary material, which is available to authorized users.

Patients with systemic sclerosis-associated pulmonary arterial hypertension express a genomic signature distinct from patients with interstitial lung disease

“…Another S100A protein, S100A4, activates advance glycation end-products receptor (RAGE) leading to activation of STAT3 and decreased bone morphogenetic protein receptor-2 (BMPR2) activity in human pulmonary artery smooth muscle cells (14). In a recent multi-organ multi-network analysis of tissues from SSc patients, S100A genes, and multiple genes involved in cell cycle control, apoptosis, extracellular matrix remodeling (including TIMP1), innate immunity, and response to TGF-β were associated with SSc-PAH and SSc-ILD (15). Therefore, we hypothesize that S100P represents a common pathogenic link between SSc-PAH and SSc-ILD, which may be mediated through interactions with S100A proteins.…”

Black, White, and Gray: Macrophages in Skin Repair and Disease

“…These macrophages produce fibrogenic cytokines such as TGFβ and promote neovascularization 89,90 . Many of these studies are outcomes of in vitro observations or analysis of a limited number of surface markers, although more recently they are supported by unbiased genome-wide analyses 91 . Despite the promising findings, the pathways that govern activation of the macrophages in scleroderma are still unknown and remain an active area of investigation.…”

The Mechanistic Implications of Gene Expression Studies in SSc: Insights From Systems Biology

“…Further work investigated whether the molecular patterns perturbed in skin were similar to those disrupted in other tissues, including esophagus and lung [10] (discussed in detail in “Systems biology of SSc, data integration, and the importance of public data” below). These data suggest that intrinsic molecular subsets are a common feature of skin and esophagus in patients with SSc and may share expression patterns with one another and other tissues.…”

“…Furthermore, subsets have been observed in a small study of esophagus [9]. A recent multi-tissue study also suggests that inflammatory subsets found in skin and esophagus share underlying gene expression patterns and pathways with fibrotic lung disease [10]. …”

“…Some early studies have identified patterns in cell types thought to drive disease that are correlated with response to treatment (e.g., methylation patterns in CD4 T cells in RA [13]). Perhaps the most important recent contribution of gene expression studies to SSc is the identification of specific pathways and cell types requiring further study [10,14]. These associations show significant progress towards precision medicine in SSc – a necessary prelude to optimizing clinical practice – that is rooted in an understanding of disease mechanism.…”