4.8 Article

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

期刊

CELL REPORTS
卷 35, 期 11, 页码 -

出版社

CELL PRESS
DOI: 10.1016/j.celrep.2021.109246

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资金

  1. Novo Nordisk Foundation (NNF) [NNF15CC0018346]
  2. University of Copenhagen (UCPH)
  3. Karolinska Institute
  4. Canadian Institutes of Health Research (CIHR) [FDN-148431]
  5. National Institute for Health Research (NIHR) Oxford Biomedical Research Centre
  6. PRIME from the Japan Agency for Medical Research and Development (AMED) [JP18gm5910013]
  7. LEAP from the Japan Agency for Medical Research and Development (AMED)
  8. [NNF140C0013655]
  9. [NNF10CC1016515]

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The study identifies that succinate regulates transcription of immune function genes by activating Gq signaling, affecting the phenotype of macrophages M2 and M1. This indicates that SUCNR1 acts as a transcriptional regulator in macrophages.
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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