Succinate aggravates pulmonary fibrosis through the succinate/SUCNR1 axis

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease that leads to destruction of alveoli and replacement by fibrotic tissue. Metabolic profiling of lung tissue and serum from patients with IPF has revealed that levels of tricarboxylic acid cycle metabolites such as succinate are altered in patients with IPF. In our study, we aim to evaluate the role of succinate and its receptor-succinate receptor 1 (SUCNR1) in the pathogenesis of lung fibrosis, with a focus on fibroblasts, a central cell in IPF. SUCNR1 expression was investigated by using Western blots, qPCR, and in situ hybridisation. In vitro assays with IPF and normal human lung fibroblasts (NHLF) were used to evaluate the effect of succinate treatment on the expression of fibrotic markers, fibroblast-myofibroblast transition, apoptosis, and signaling mechanisms. Studies with the bleomycin mouse model of pulmonary fibrosis were used to evaluate the effect of succinate in vivo. Several cell types in the lung express SUCNR1 including alveolar type II cells, fibroblasts, and macrophages. In IPF patient fibroblasts, succinate treatment increased the expression of fibrosis-associated markers, such as alpha-smooth muscle actin and collagen. Moreover, succinate exaggerated transforming growth factor-beta (TGF-β)-mediated fibroblast-to-myofibroblast transition in NHLF. In vivo, succinate treatment significantly increased collagen accumulation in the lung and enhanced weight loss in bleomycin-treated mice. Importantly, succinate-mediated elevation of fibrosis-associated markers was lost upon knockdown of SUCNR1 or inhibition of ERK activation in IPF patient-derived fibroblasts. Succinate exerted profibrotic effects in vitro and in vivo. Thus, SUCNR1 antagonism may be a potential therapeutic target for the treatment of IPF.<b>NEW & NOTEWORTHY</b> This paper highlights the role of the succinate/SUCNR1 axis in pulmonary fibrosis. Receptor activation leads to profibrotic changes in IPF patient-derived fibroblasts. This finding could also be replicated in a mouse model of pulmonary fibrosis.