Extracellular Succinate Hyperpolarizes M2 Macrophages through SUCNR1/GPR91-Mediated Gq Signaling

Succinate functions both as a classical TCA cycle metabolite and as 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 surprisingly identify Gq rather than Gi signaling, to be responsible for SUCNR1-mediated effects on basic transcriptional regulation. Importantly, in primary human M2 macrophages, where 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. Overall design: RNA-seq of primary human monocyte-derived macrophages from healthy adult donors. Macrophages were polarised to the M2 state and treated with succinate +/- a SUCNR1 antagonist or a Gq inhibitor and compared with a vehicle control.