CD146 Associates with Gp130 to Control a Macrophage Pro-inflammatory Program That Regulates the Metabolic Response to Obesity.
CD146 Associates with Gp130 to Control a Macrophage Pro-inflammatory Program That Regulates the Metabolic Response to Obesity.
复制标题
DOI：
10.1002/advs.202103719
复制
发表时间：
2022-05
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
肥胖相关代谢功能障碍的机制涉及全身炎症的发展，主要由巨噬细胞介导。将M1样脂肪组织巨噬细胞（ATMs）转换为M2样ATMs，这是一群与体重减轻和胰岛素敏感性相关的巨噬细胞，被认为是治疗肥胖相关代谢综合征的可行策略。然而，重建atm机两极分化的机制仍然难以捉摸。这项研究表明，CD146+ ATMs在饮食诱导的肥胖过程中在脂肪组织中积累，并与体重增加、全身炎症和肥胖诱导的胰岛素抵抗有关。灭活巨噬细胞CD146基因或靶向CD146的抗体可减轻肥胖相关的慢性炎症和代谢功能障碍。巨噬细胞CD146与糖蛋白130 （Gp130）相互作用，Gp130是白细胞介素- 6细胞因子家族受体信号复合物的共同亚基。CD146/Gp130相互作用通过激活JNK信号和抑制STAT3 （M2样极化的转录因子）的激活来促进atm的促炎极化。通过抗CD146抗体或白细胞介素- 6破坏它们的相互作用，使atm朝着抗炎极化方向发展，从而减轻肥胖诱导的小鼠慢性炎症和代谢功能障碍。结果表明，巨噬细胞CD146是促炎极化的重要决定因素，在肥胖诱导的代谢功能障碍中起关键作用。CD146可能成为治疗肥胖并发症的新靶点。在高脂血症条件下，CD146与Gp130相互作用抑制ACM（主要是IL - 6）诱导的STAT3激活。它还激活JNK信号，促进M1相关基因和SOCS3的表达，从而增强STAT3的抑制作用。缺失或阻断CD146使atm向着抗炎极化方向发展，从而减轻肥胖引起的慢性炎症和代谢功能障碍。
The mechanism of obesity‐related metabolic dysfunction involves the development of systemic inflammation, largely mediated by macrophages. Switching of M1‐like adipose tissue macrophages (ATMs) to M2‐like ATMs, a population of macrophages associated with weight loss and insulin sensitivity, is considered a viable therapeutic strategy for obesity‐related metabolic syndrome. However, mechanisms for reestablishing the polarization of ATMs remain elusive. This study demonstrates that CD146+ ATMs accumulate in adipose tissue during diet‐induced obesity and are associated with increased body weight, systemic inflammation, and obesity‐induced insulin resistance. Inactivating the macrophage CD146 gene or antibody targeting of CD146 alleviates obesity‐related chronic inflammation and metabolic dysfunction. Macrophage CD146 interacts with Glycoprotein 130 (Gp130), the common subunit of the receptor signaling complex for the interleukin‐6 family of cytokines. CD146/Gp130 interaction promotes pro‐inflammatory polarization of ATMs by activating JNK signaling and inhibiting the activation of STAT3, a transcription factor for M2‐like polarization. Disruption of their interaction by anti‐CD146 antibody or interleukin‐6 steers ATMs toward anti‐inflammatory polarization, thus attenuating obesity‐induced chronic inflammation and metabolic dysfunction in mice. The results suggest that macrophage CD146 is an important determinant of pro‐inflammatory polarization and plays a pivotal role in obesity‐induced metabolic dysfunction. CD146 could constitute a novel therapeutic target for obesity complications. Under hyperlipidemia conditions, CD146 interacts with Gp130 to inhibit ACM (mainly IL‐6)‐induced STAT3 activation. It also activates the JNK signal and promotes the expression of M1‐related genes and SOCS3, which enhances the STAT3 inhibition. Deletion or blocking CD146 steers ATMs toward anti‐inflammatory polarization, thus attenuating obesity‐induced chronic inflammation and metabolic dysfunction.