Extracellular succinate hyperpolarizes M2 macrophages through SUCNR1/GPR91-mediated Gq signaling.
Cell Rep
; 35(11): 109246, 2021 06 15.
Article
em En
| MEDLINE
| ID: mdl-34133934
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.
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MEDLINE
Assunto principal:
Transdução de Sinais
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Ácido Succínico
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Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP
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Receptores Acoplados a Proteínas G
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Espaço Extracelular
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Macrófagos
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article