Repositori URV

Identifier: imarina:4899351

Handle: https://hdl.handle.net/20.500.11797/imarina4899351

Authors:
Keiran N, Ceperuelo-Mallafré V, Calvo E, Hernández-Alvarez MI, Ejarque M, Núñez-Roa C, Horrillo D, Maymó-Masip E, Rodríguez MM, Fradera R, de la Rosa JV, Jorba R, Megia A, Zorzano A, Medina-Gómez G, Serena C, Castrillo A, Vendrell J, Fernández-Veledo S

Abstract:
Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a pro-inflammatory program; however, the contribution of SUCNR1 to macrophage phenotype and function has remained unclear. Here we found that activation of SUCNR1 had a critical role in the anti-inflammatory responses in macrophages. Myeloid-specific deficiency in SUCNR1 promoted a local pro-inflammatory phenotype, disrupted glucose homeostasis in mice fed a normal chow diet, exacerbated the metabolic consequences of diet-induced obesity and impaired adipose-tissue browning in response to cold exposure. Activation of SUCNR1 promoted an anti-inflammatory phenotype in macrophages and boosted the response of these cells to type 2 cytokines, including interleukin-4. Succinate decreased the expression of inflammatory markers in adipose tissue from lean human subjects but not that from obese subjects, who had lower expression of SUCNR1 in adipose-tissue-resident macrophages. Our findings highlight the importance of succinate-SUCNR1 signaling in determining macrophage polarization and assign a role to succinate in limiting inflammation.