Extracellular succinate hyperpolarizes M2 macrophages through SUCNR1/GPR91-mediated Gq signaling
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Extracellular succinate hyperpolarizes M2 macrophages through SUCNR1/GPR91-mediated Gq signaling. / Trauelsen, Mette; Hiron, Thomas K.; Lin, Da; Petersen, Jacob E.; Breton, Billy; Husted, Anna Sofie; Hjorth, Siv A.; Inoue, Asuka; Frimurer, Thomas M.; Bouvier, Michel; O'Callaghan, Chris A.; Schwartz, Thue W.
In: Cell Reports, Vol. 35, No. 11, 109246, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Extracellular succinate hyperpolarizes M2 macrophages through SUCNR1/GPR91-mediated Gq signaling
AU - Trauelsen, Mette
AU - Hiron, Thomas K.
AU - Lin, Da
AU - Petersen, Jacob E.
AU - Breton, Billy
AU - Husted, Anna Sofie
AU - Hjorth, Siv A.
AU - Inoue, Asuka
AU - Frimurer, Thomas M.
AU - Bouvier, Michel
AU - O'Callaghan, Chris A.
AU - Schwartz, Thue W.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - G protein
KW - GPR91
KW - Gq signaling
KW - M2 macrophages
KW - non-metabolite ligands
KW - succinate
KW - SUCNR1
U2 - 10.1016/j.celrep.2021.109246
DO - 10.1016/j.celrep.2021.109246
M3 - Journal article
C2 - 34133934
AN - SCOPUS:85107987154
VL - 35
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 11
M1 - 109246
ER -
ID: 272642834