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

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-metabol...

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Bibliographic Details
Published in:Cell reports (Cambridge) 2021-06, Vol.35 (11), p.109246-109246, Article 109246
Main Authors: 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
Format: Article
Language:English
Subjects:
Arrestins - metabolism
Extracellular Space - chemistry
Female
G protein
Gene Expression Regulation
Gene Ontology
GPR91
Gq signaling
GTP-Binding Protein alpha Subunits, Gi-Go - metabolism
GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism
HEK293 Cells
Humans
Ligands
M2 macrophages
Macrophages - immunology
Macrophages - metabolism
Male
Models, Biological
Protein Subunits - metabolism
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - genetics
Receptors, G-Protein-Coupled - metabolism
Signal Transduction
succinate
Succinic Acid - metabolism
SUCNR1
Transcriptional Activation - genetics
Type C Phospholipases - metabolism
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Summary: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.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2021.109246