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RNA-sequencing of FACS-sorted hematopoietic stem and progenitor cells (LSK) from bone marrow of WT and Sucnr1 knock-out mice

ABSTRACT: Succinate is a metabolic signal that links hypoxia to IL-1β and cell responses in myeloid cells through intracellular mechanisms, but also autocrine/paracrine processes through succinate receptor 1 (Sucnr1). Succinate and its receptor have been scarcely studied in the context of hematopoiesis under health or disease. We investigated the in vivo role and molecular mechanisms of succinate and Sucnr1 in normal and malignant hematopoiesis, using an in vivo knock-out (KO) of Sucnr1.

ORGANISM(S): Mus musculus

PROVIDER: GSE215255 | GEO | 2025/12/02

REPOSITORIES: GEO

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Extracellular Succinate Hyperpolarizes M2 Macrophages through SUCNR1/GPR91-Mediated Gq Signaling

Project description:Succinate functions both as a classical TCA cycle metabolite and as 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 surprisingly identify Gq rather than Gi signaling, to be responsible for SUCNR1-mediated effects on basic transcriptional regulation. Importantly, in primary human M2 macrophages, where 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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Project description:The concept of “signaling metabolites” in the control of metabolic homeostasis is gaining traction. The Krebs cycle substrate succinate, a pleiotropic metabolite that acts akin to hormones and cytokines through succinate receptor 1 (SUCNR1, also known as GPR91), is one example of this new class of metabolites. SUCNR1 has a broad expression and is highly abundant in white adipose tissue. It was a general assumption that SUCNR1 is functionally inactive in healthy tissues, and for many years, SUCNR1 was explored from an immune perspective, mainly in inflammatory-related conditions, particularly those associated with chronic hypersuccinemia. Recent studies, however, indicate that extracellular levels of succinate transiently increase in response to physiological changes such as exercise, cold exposure, or food ingestion. Succinate thus emerges as a reporter of both tissue stress and metabolism, raising the possibility of its involvement in additional metabolic functions as a hormone-like metabolite. Indeed, it is conceivable that "succinate sensing" by SUCNR1 may be part of the metabolite-sensing machinery that governs energy homeostasis. To better understand the effect of the adipocyte Sucnr1 deletion on adipose tissue, we selectively inactivated Sucnr1 in murine adipocytes and profiled the transcription state of epididymal white adipose tissue from adipocyte cell-specific Sucnr1 knockout mice (Ad-Sucnr1 KO) and control Sucnr1fl/fl mice.

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2022-02-17 | PXD024717 | Pride

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Project description:Extracellular Succinate Hyperpolarizes M2 Macrophages through SUCNR1/GPR91-Mediated Gq Signaling

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