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

Autor:	Trauelsen M; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Maersk Tower, 2200 Copenhagen, Denmark., Hiron TK; Wellcome Trust Centre for Human Genetics and NIHR Oxford Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK., Lin D; Wellcome Trust Centre for Human Genetics and NIHR Oxford Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK., Petersen JE; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Maersk Tower, 2200 Copenhagen, Denmark., Breton B; Department of Biochemistry and Molecular Medicine, Institute for Research in Immunology and Cancer, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada., Husted AS; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Maersk Tower, 2200 Copenhagen, Denmark., Hjorth SA; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Maersk Tower, 2200 Copenhagen, Denmark., Inoue A; Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan., Frimurer TM; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Maersk Tower, 2200 Copenhagen, Denmark., Bouvier M; Department of Biochemistry and Molecular Medicine, Institute for Research in Immunology and Cancer, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada., O'Callaghan CA; Wellcome Trust Centre for Human Genetics and NIHR Oxford Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK., Schwartz TW; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Maersk Tower, 2200 Copenhagen, Denmark. Electronic address: tws@sund.ku.dk.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2021 Jun 15; Vol. 35 (11), pp. 109246.
DOI:	10.1016/j.celrep.2021.109246
Abstrakt:	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. Competing Interests: Declaration of interests M.B. is the chair of the scientific advisory board for Domain Therapeutics (DT), and some of the BRET-based biosensors used in the present study were licensed to DT for commercial use. The other authors declare no competing interests. (Copyright © 2021. Published by Elsevier Inc.)
Databáze:	MEDLINE
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