Succinate aggravates pulmonary fibrosis through the succinate/SUCNR1 axis.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease, characterized by extracellular matrix (ECM) deposition leading to loss of compliance, compromising alveolar integrity and gas exchange. Transcriptomic and metabolic profiling of fibrotic lung tissue point towards dysregulation of metabolic pathways. Levels of tricarboxylic acid cycle intermediates including succinate are altered in IPF. In this study, we aim to understand the role of succinate, and its receptor SUCNR1 in IPF. Methods: SUCNR1 expression in human and mouse lung and in fibroblasts was investigated using western blots, qPCR, and FISH. In vitro assays with IPF patient derived fibroblasts were used to evaluate the effect of succinate treatment on the expression of fibrotic markers. In vivo studies with the bleomycin mouse model of PF were used to evaluate the effect of succinate on collagen accumulation and weight. Results: Several cell types in the lung express SUCNR1-mRNA including ATII cells, smooth muscle cells, fibroblasts, and macrophages. In IPF patient derived fibroblasts, succinate treatment increased expression of markers associated with fibrosis such as alpha smooth muscle actin (1.4-fold change; p=0.004) and collagen (2.6-fold change; p=0.017). In vivo, succinate treatment significantly increased collagen accumulation (1.5-fold change; p=0.02) in bleomycin treated mice compared to mice treated with saline. Moreover, succinate treatment exaggerated weight loss in the bleomycin treated mice. Conclusion: Succinate exerted pro-fibrotic effects in vitro and in vivo. Deciphering the mechanisms involved will be key to investigating SUCNR1 as a potential therapeutic target.