Abstract
BackgroundScleroderma (SSc) is a rare autoimmune disease characterized by vascular impairment and progressive fibrosis of the skin and other organs. Oncostatin M, a member of the IL-6 family, is elevated in SSc serum and was recognized as a significant player in various stages of fibrosis. The goal of this study was to assess the contribution of the OSM/OSMRβ pathway to endothelial cell (EC) injury and activation in SSc.MethodsIHC and IF were used to assess the distribution of OSM and OSMRβ in SSc (n = 14) and healthy control (n = 7) skin biopsies. Cell culture experiments were performed in human dermal microvascular endothelial cells (HDMECs) and included mRNA and protein analysis, and cell migration and proliferation assays. Ex vivo skin organoid culture was used to evaluate the effect of OSM on perivascular fibrosis.ResultsOSMRβ protein was elevated in dermal ECs and in fibroblasts of SSc patients. Treatments of HDMECs with OSM or IL-6+sIL-6R have demonstrated that both cytokines similarly stimulated proinflammatory genes and genes related to endothelial to mesenchymal transition (EndMT). OSM was more effective than IL-6+sIL-6R in inducing cell migration, while both treatments similarly induced cell proliferation. The effects of OSM were mediated via OSMRβ and STAT3, while the LIFR did not contribute to these responses. Both OSM and IL-6+sIL-6R induced profibrotic gene expression in HDMECs, as well as expansion of the perivascular PDGFRβ+ cells in the ex vivo human skin culture system. Additional studies in HDMECs showed that siRNA-mediated downregulation of FLI1 and its close homolog ERG resulted in increased expression of OSMRβ in HDMECs.ConclusionsThis work provides new insights into the role of the OSM/OSMRβ axis in activation/injury of dermal ECs and supports the involvement of this pathway in SSc vascular disease.
Highlights
Scleroderma known as systemic sclerosis (SSc) is a complex chronic multisystem disease of unknown etiology that is characterized by early vascular damage with activation of the immune system, followed by skin and internal organ fibrosis [1]
Double immunofluorescence of Oncostatin M receptor beta (OSMRβ) and CD31 confirmed the presence of OSMRβ on endothelial cells (ECs) (Fig. 1c)
These results suggest that increased expression of OSMRβ on ECs could contribute to the process of vasculopathy in the skin of SSc patients
Summary
Scleroderma known as systemic sclerosis (SSc) is a complex chronic multisystem disease of unknown etiology that is characterized by early vascular damage with activation of the immune system, followed by skin and internal organ fibrosis [1]. The IL-6 cytokine family encompasses a group of pleiotropic cytokines produced by a variety of cells in response to inflammatory stimuli [7] This cytokine family shares a common signal transducer gp130 in the receptor complex. Increased levels of IL-6 family members, including oncostatin M (OSM) and IL-6, have been reported in many pathological conditions characterized by chronic inflammation, vascular injury, and fibrosis including SSc [8]. OSM was shown to play an important role in various stages of the fibrotic process including inflammation and activation of fibroblasts [11, 12]. The goal of this study was to assess the contribution of the OSM/OSMRβ pathway to endothelial cell (EC) injury and activation in SSc
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