GPR120 regulates neutrophil functions and intestinal homeostasis

Abstract GPR120 (also known as free fatty acid receptor 4, FFAR4) has been identified recently as a bona fide receptor for long-chain fatty acids (LCFA), and has a critical role in various physiological homeostasis mechanisms such as adipogenesis. However, if and how GPR120 regulates intestinal homeostasis is still largely unknown. In this study, we found that GPR120−/− mice showed more severe colitis induced by DSS compared to WT mice, which was evident as increased weight loss and higher histopathology scores. Depletion of neutrophils with anti-Ly6G increased the colitis severity, indicating protective roles of GPR120 and neutrophils in the intestines from inflammation. GPR120 agonist, CpdA, promoted neutrophil production of IL-17 and IL-22, but not TNF-α and TGF-β expression. Consistently, GPR120−/− neutrophils showed impaired IL-17 and IL-22 production compared with WT neutrophils. Additionally, treatment with CpdA and LCFA Omega-3, DHA, enhanced neutrophil production of reactive oxygen species (ROS). Furthermore, CpdA increased antimicrobial peptide S100A9, but not S100A8, production in neutrophils. Mechanically, inhibition of mTOR pathway by mTOR inhibitors, rapamycin and AZD8055, suppressed neutrophil IL-22 and IL-17 production induced by CpdA, while it did not affect the GPR120 agonist induction of ROS. Additionally, inhibition of glycolysis by glycolysis inhibitor 2-DG suppressed GPR120 agonist-induced IL-17 but not IL-22 and ROS production in neutrophils, indicating mTOR and glycolysis differentially regulate GPR120 induction of IL-17, IL-22 and ROS. Taken together, our results highlight a critical role of GPR120 in regulating neutrophil functions, thus contributing to the maintenance of intestinal homeostasis.