@article{3fbfb763cb434bdc9afc903be04b2ada,
title = "Extracellular succinate hyperpolarizes M2 macrophages through SUCNR1/GPR91-mediated Gq signaling",
abstract = "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.",
keywords = "G protein, GPR91, Gq signaling, M2 macrophages, SUCNR1, non-metabolite ligands, succinate",
author = "Mette Trauelsen and Hiron, {Thomas K.} and Da Lin and Petersen, {Jacob E.} and Billy Breton and Husted, {Anna Sofie} and Hjorth, {Siv A.} and Asuka Inoue and Frimurer, {Thomas M.} and Michel Bouvier and O'Callaghan, {Chris A.} and Schwartz, {Thue W.}",
note = "Funding Information: We thank Marianne G. Johansen for expert technical assistance and Signe Mathiasen and Jonathan Javitch, Columbia University, for help in setting up the Gα subunit gene-edited HEK293 cells. The work was supported by grant NNF15CC0018346 from the Novo Nordisk Foundation (NNF) to the University of Oxford, University of Copenhagen (UCPH), and Karolinska Institute and by Challenge Grant NNF140C0013655 (T.W.S.). The Center for Basic Metabolic Research (CBMR) is supported by grant NNF10CC1016515 . M.B. is supported by grant FDN-148431 from the Canadian Institutes of Health Research (CIHR). A.I. was funded by PRIME ( JP18gm5910013 ) and LEAP ( JP18gm0010004 ) from the Japan Agency for Medical Research and Development (AMED). The research was also supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. Publisher Copyright: {\textcopyright} 2021",
year = "2021",
month = jun,
day = "15",
doi = "10.1016/j.celrep.2021.109246",
language = "English",
volume = "35",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",
}