期刊
NATURE IMMUNOLOGY
卷 20, 期 5, 页码 581-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41590-019-0372-7
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资金
- Spanish Ministry of Science, Innovation and Universities - European Regional Development Fund (ERDF) [PI14/00228, PI17/01503, SAF2015-65019-R, SAF2014-56819-R, SAF2015-71878-REDT, BFU2016-78951-R, PI15/00143, PI15/01562, BFU2015-70454-REDT, BFU2017-90578-REDT]
- MINECO, Spain (FPI) [BES-2016-077745]
- 'Ramon y Cajal' program from MINECO [RYC2013-13186]
- Miguel Servet tenure-track program from the Fondo de Investigacion Sanitaria [CP10/00438, CPII16/00008]
- ERDF
- BioBank IISPV [PT17/0015/0029]
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.
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