The medium-chain fatty acid receptor GPR84 mediates myeloid cell infiltration promoting steatohepatitis and fibrosis

Abstract

Medium-chain fatty acids (MCFAs) have been associated with anti-steatotic effects in hepatocytes. Expression of the MCFA receptor GPR84 (G protein-coupled receptor 84) is induced in immune cells under inflammatory conditions and can promote fibrogenesis. We aimed at deciphering the role of GPR84 in the pathogenesis of non-alcoholic steatohepatitis (NASH), exploring its potential as a therapeutic target. GPR84 expression is upregulated in liver from patients with non-alcoholic fatty liver disease (NAFLD), correlating with the histological degree of inflammation and fibrosis. In mouse and human, activated monocytes and neutrophils upregulate GPR84 expression. Chemotaxis of these myeloid cells by GPR84 stimulation is inhibited by two novel, small molecule GPR84 antagonists. Upon acute liver injury in mice, treatment with GPR84 antagonists significantly reduced the hepatic recruitment of neutrophils, monocytes, and monocyte-derived macrophages (MoMF). We, therefore, evaluated the therapeutic inhibition of GPR84 by these two novel antagonists in comparison to selonsertib, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, in three NASH mouse models. Pharmacological inhibition of GPR84 significantly reduced macrophage accumulation and ameliorated inflammation and fibrosis, to an extent similar to selonsertib. In conclusion, our findings support that GPR84 mediates myeloid cell infiltration in liver injury and is a promising therapeutic target in steatohepatitis and fibrosis.