Extracellular succinate hyperpolarizes M2 macrophages through SUCNR1/GPR91-mediated Gq signaling

• Main Authors: Mette Trauelsen, Thomas K. Hiron, Da Lin, Jacob E. Petersen, Billy Breton, Anna Sofie Husted, Siv A. Hjorth, Asuka Inoue, Thomas M. Frimurer, Michel Bouvier, Chris A. O’Callaghan, Thue W. Schwartz
• Format: Article
• Language: English
• Published: Elsevier 2021-06-01
• Series: Cell Reports
• Subjects: GPR91; SUCNR1; succinate; M2 macrophages; G protein; Gq signaling
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124721006112

Summary: Succinate functions both as a classical TCA cycle metabolite and an extracellular metabolic stress signal sensed by the mainly Gi-coupled succinate receptor SUCNR1. In the present study, we characterize and compare effects and signaling pathways activated by succinate and both classes of non-metabolite SUCNR1 agonists. By use of specific receptor and pathway inhibitors, rescue in G-protein-depleted cells and monitoring of receptor G protein activation by BRET, we identify Gq rather than Gi signaling to be responsible for SUCNR1-mediated effects on basic transcriptional regulation. Importantly, in primary human M2 macrophages, in which SUCNR1 is highly expressed, we demonstrate that physiological concentrations of extracellular succinate act through SUCNR1-activated Gq signaling to efficiently regulate transcription of immune function genes in a manner that hyperpolarizes their M2 versus M1 phenotype. Thus, sensing of stress-induced extracellular succinate by SUCNR1 is an important transcriptional regulator in human M2 macrophages through Gq signaling.