Characterization of Long Non-Coding RNAs in Systemic Sclerosis Monocytes: A Potential Role for PSMB8-AS1 in Altered Cytokine Secretion

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.

The Roles of Noncoding RNAs in Systemic Sclerosis

“…LncPSMB8-AS1 is also upregulated in the blood monocytes of patients with early SSc, ncSSc and dsSSc and is implicated in immune cell activation and vesicle-related transport. PSMB8-AS1 knockdown resulted in decreased concentrations of IL-6 and TNFa in the cell-free supernatant (58), which are linked to fibrotic (80,81), and ILD (82,83). Thus, PSMB8-AS1 can modulate monocyte activation in SSc and secretion of proinflammatory cytokines (58).…”

“…PSMB8-AS1 knockdown resulted in decreased concentrations of IL-6 and TNFa in the cell-free supernatant (58), which are linked to fibrotic (80,81), and ILD (82,83). Thus, PSMB8-AS1 can modulate monocyte activation in SSc and secretion of proinflammatory cytokines (58).…”

Long noncoding RNAs in respiratory viruses: A review

“… 54 The upregulation of PSMB8‐AS1 can modulate the secretion of IL‐6 and tumour necrosis factor (TNF) α, two pivotal proinflammatory cytokines. 55 It is concluded that lnc‐PSMB8‐AS1 can be used as a novel host factor for developing antiviral therapy against influenza virus infection. 56 …”

Epigenetic Modifications in the Pathogenesis of Systemic Sclerosis

“… 95 The differentially expressed ncRNA00201 and PSMB8-AS1 in blood and MGC12916 in fibroblasts were also confirmed to be important players in the pathogenesis of SSc. 40 , 96 , 97 The involvement of lncRNAs in the pathogenesis of scleroderma is intricate and complicated, which may be through the epigenetic regulation of the gene itself, interacting with miRNAs, or affecting the secretion of important cytokines such as IL-6 and TNFα, 97 and participating in regulating the expression of fibrosis-related genes. At present, the field of lncRNA is still in its infancy, and related research is still limited but proved to be effective.…”