Abstract
Systemic sclerosis (SSc) is a chronic autoimmune disease mainly affecting the connective tissue. In SSc patients, monocytes are increased in circulation, infiltrate affected tissues, and show a pro-inflammatory activation status, including the so-called interferon (IFN) signature. We previously demonstrated that the dysregulation of the IFN response in SSc monocytes is sustained by altered epigenetic factors as well as by upregulation of the long non-coding RNA (lncRNA) NRIR. Considering the enormously diverse molecular functions of lncRNAs in immune regulation, the present study investigated the genome-wide profile of lncRNAs in SSc monocytes, with the aim to further unravel their possible role in monocyte dysregulation and disease pathogenesis. Transcriptomic data from two independent cohorts of SSc patients identified 886 lncRNAs with an altered expression in SSc monocytes. Differentially expressed lncRNAs were correlated with neighboring protein coding genes implicated in the regulation of IFN responses and apoptotic signaling in SSc monocytes. In parallel, gene co-expression network analysis identified the lncRNA PSMB8-AS1 as a top-ranking hub gene in co-expression modules implicated in cell activation and response to viral and external stimuli. Functional characterization of PSMB8-AS1 in monocytes demonstrated that this lncRNA is involved in the secretion of IL-6 and TNFα, two pivotal pro-inflammatory cytokines altered in the circulation of SSc patients and associated with fibrosis and disease severity. Collectively, our data showed that lncRNAs are linked to monocyte dysregulation in SSc, and highlight their potential contribution to disease pathogenesis.
Highlights
Exploiting transcriptomic data of monocytes obtained from Systemic sclerosis (SSc) patients and matched healthy controls, we identified multiple long non-coding RNA (lncRNA) potentially involved in the regulation of apoptotic pathways and IFN signaling in SSc monocytes
The genome-wide expression profile of lncRNAs in healthy and SSc monocytes was initially assessed in the “Definite SSc cohort”, comprising non-cutaneous SSc (ncSSc) (n = 7), lcSSc (n = 11) and diffuse-cutaneous SSc (dcSSc) (n = 7) patients, and matched healthy controls (n = 9, Table 1)
The aim of this study was to investigate the potential role of the dysregulation of SSc monocytes, an important cell type implicated in SSc pathogenesis
Summary
Systemic sclerosis (SSc) is a chronic autoimmune disease with a highly heterogeneous clinical phenotype [1]. The disease is characterized by three main hallmarks: vascular abnormalities, immune system dysregulation, and fibrosis. Based on the extent of skin fibrosis and the presence of vascular and immunological abnormalities, SSc patients can be divided into four subsets: early SSc (eaSSc), non-cutaneous SSc (ncSSc), limited-cutaneous. SSc (lcSSc), and diffuse-cutaneous SSc (dcSSc) [2,3]. Vascular abnormalities characterize the pre-clinical stage of SSc, and Raynaud’s Phenomenon (RP) occurs in 90–98% of patients with
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