Choi Cheoljun, Saha Abhirup, An Seungchan, Cho Yoon Keun, Kim Heeseong, Noh Minsoo, Lee Yun-Hee
College of Pharmacy and Research Institute of Pharmaceutical Sciences Seoul National University, Seoul, South Korea.
Front Cell Dev Biol. 2022 Jun 21;10:925971. doi: 10.3389/fcell.2022.925971. eCollection 2022.
Adipose tissue macrophages are a major immune cell type contributing to homeostatic maintenance and pathological adipose tissue remodeling. However, the mechanisms underlying macrophage recruitment and polarization in adipose tissue during obesity remain poorly understood. Previous studies have suggested that the gap junctional protein, connexin 43 (Cx43), plays a critical role in macrophage activation and phagocytosis. Herein, we investigated the macrophage-specific roles of Cx43 in high fat diet (HFD)-induced pathological remodeling of adipose tissue. Expression levels of Cx43 were upregulated in macrophages co-cultured with dying adipocytes , as well as in macrophages associated with dying adipocytes in the adipose tissue of HFD-fed mice. Cx43 knockdown reduced lipopolysaccharide (LPS)-induced ATP release from macrophages and decreased inflammatory responses of macrophages co-cultured with dying adipocytes. Based on global gene expression profiling, macrophage-specific Cx43-knockout (Cx43-MKO) mice were resistant to HFD-induced inflammatory responses in adipose tissue, potentially P2X7-mediated signaling pathways. Cx43-MKO mice exhibited reduced HFD-induced macrophage recruitment in adipose tissue. Moreover, Cx43-MKO mice showed reduced inflammasome activation in adipose tissues and improved glucose tolerance. Collectively, these findings demonstrate that Cx43 expression in macrophages facilitates inflammasome activation, which, in turn, contributes to HFD-induced metabolic dysfunction.
脂肪组织巨噬细胞是一种主要的免疫细胞类型，有助于体内稳态维持和病理性脂肪组织重塑。然而，肥胖期间脂肪组织中巨噬细胞募集和极化的潜在机制仍知之甚少。先前的研究表明，间隙连接蛋白连接蛋白43（Cx43）在巨噬细胞激活和吞噬作用中起关键作用。在此，我们研究了Cx43在高脂饮食（HFD）诱导的脂肪组织病理性重塑中的巨噬细胞特异性作用。在与濒死脂肪细胞共培养的巨噬细胞中，以及在高脂饮食喂养小鼠脂肪组织中与濒死脂肪细胞相关的巨噬细胞中，Cx43的表达水平上调。Cx43基因敲低减少了脂多糖（LPS）诱导的巨噬细胞ATP释放，并降低了与濒死脂肪细胞共培养的巨噬细胞的炎症反应。基于全基因组表达谱分析，巨噬细胞特异性Cx43基因敲除（Cx43-MKO）小鼠对高脂饮食诱导的脂肪组织炎症反应具有抗性，可能是通过P2X7介导的信号通路。Cx43-MKO小鼠在脂肪组织中高脂饮食诱导的巨噬细胞募集减少。此外，Cx43-MKO小鼠脂肪组织中的炎性小体激活减少，葡萄糖耐量改善。总的来说，这些发现表明巨噬细胞中Cx43的表达促进了炎性小体激活，进而导致高脂饮食诱导的代谢功能障碍。
