Oxidative stress-induced senescence mediates inflammatory and fibrotic phenotypes in fibroblasts from systemic sclerosis patients.

Rheumatology
Ozge Kizilay ManciniMarc J Servant

Abstract

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by inflammation and fibrosis. Although constitutive activation of fibroblasts is proposed to be responsible for the fibrotic and inflammatory features of the disease, the underlying mechanism remains elusive and, effective therapeutic targets are still lacking. The aim of this study was to evaluate the role of oxidative stress-induced senescence and its contribution to the pro-fibrotic and pro-inflammatory phenotypes of fibroblasts from SSc patients. Dermal fibroblasts were isolated from SSc (n = 13) and healthy (n = 10) donors. Fibroblast's intracellular and mitochondrial reactive oxygen species were determined by flow cytometry. Mitochondrial function measured by Seahorse XF24 analyzer. Fibrotic and inflammatory gene expressions were assessed by qPCR and key pro-inflammatory components of the fibroblasts' secretome (interleukin (IL) 6 and IL8) were quantified by ELISA. Compared to healthy fibroblasts, SSc fibroblasts displayed higher levels of both intracellular and mitochondrial ROS. Oxidative stress in SSc fibroblasts induced the expression of fibrotic genes and activated the transforming growth factor-β-activated kinase 1 (TAK1) -IκB kinase ...Continue Reading

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