Unitat de Recerca, Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain.
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
Nat Immunol. 2019 May;20(5):581-592. doi: 10.1038/s41590-019-0372-7. Epub 2019 Apr 8.
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.
琥珀酸是一种可被细胞外琥珀酸受体 1（SUNCR1）感知的信号代谢物。众所周知，巨噬细胞中琥珀酸的积累会激活促炎程序；然而，SUCNR1 对巨噬细胞表型和功能的贡献仍不清楚。在这里，我们发现 SUCNR1 的激活在巨噬细胞的抗炎反应中起着关键作用。髓系特异性 SUCNR1 缺失促进了局部促炎表型，破坏了正常饮食喂养的小鼠的葡萄糖稳态，加剧了饮食诱导肥胖的代谢后果，并损害了对寒冷暴露的脂肪组织褐变反应。SUCNR1 的激活促进了巨噬细胞的抗炎表型，并增强了这些细胞对 2 型细胞因子（包括白细胞介素 4）的反应。琥珀酸降低了瘦人脂肪组织中炎症标志物的表达，但对肥胖者没有降低，肥胖者脂肪组织驻留巨噬细胞中的 SUCNR1 表达水平较低。我们的研究结果强调了琥珀酸-SUCNR1 信号在决定巨噬细胞极化中的重要性，并将琥珀酸在限制炎症中的作用确定下来。
