Publications by authors named "Nesrine Fazez"

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

Rheumatology (Oxford) 2021 Jun 11. Epub 2021 Jun 11.

Faculty of Pharmacy, Université de Montréal, Québec, Canada.

Objective: 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.

Methods: 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.

Results: 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 β (IKKβ)- interferon regulatory factor 5 (IRF5) inflammatory signaling cascade. These cellular responses paralleled the presence of a DNA damage response, a senescence-associated secretory phenotype and a fibrotic response. Treatment of SSc fibroblasts with ROS scavengers reduced their pro-inflammatory secretome production and fibrotic gene expression.

Conclusions: Oxidative stress-induced cellular senescence in SSc fibroblasts underlies their pro-inflammatory and pro-fibrotic phenotypes. Targeting redox imbalance of SSc fibroblasts enhances their in vitro functions and could be of relevance for SSc therapy.
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June 2021