Macrophage foam cell formation and inflammation are a pathological hallmark of atherosclerosis. ClC-2 has been implicated in various pathological processes, including inflammation and lipid metabolic disorder. However, the functional role of ClC-2 in macrophage foam cell formation and inflammation is unclear. Here, we found that ClC-2 was dominantly expressed in macrophages of atherosclerotic plaque and increased in atherogenesis. Knockdown of ClC-2 inhibited ox-LDL -induced lipid uptake and deposition in macrophages. The increase in CD36 expression and the decrease in ABCA1 expression induced by ox-LDL were alleviated by ClC-2 downregulation. Further, ClC-2 lacking limited the ox-LDL-induced secretion of inflammatory cytokines and chemokine, and suppressed Nlrp3 inflammasome activation. Restoration of Nlrp3 expression reversed the effect of ClC-2 downregulation on macrophage lipid accumulation and inflammation. Collectively, our study demonstrates that ClC-2 knockdown ameliorates ox-LDL-induced macrophage foam cell formation and inflammation by inhibiting Nlrp3 inflammasome activation.

巨噬细胞泡沫细胞的形成和炎症是动脉粥样硬化的病理标志。ClC-2与多种病理过程有关，包括炎症和脂质代谢紊乱。但是，ClC-2在巨噬细胞泡沫细胞形成和炎症中的功能作用尚不清楚。在这里，我们发现ClC-2主要在动脉粥样硬化斑块的巨噬细胞中表达，并在动脉粥样硬化中增加。抑制ClC-2抑制了ox-LDL诱导的巨噬细胞脂质摄取和沉积。ox-LDL诱导的CD36表达增加和ABCA1表达减少通过ClC-2下调得到缓解。此外，ClC-2缺乏限制ox-LDL诱导的炎性细胞因子和趋化因子的分泌，并抑制Nlrp3炎性体的激活。Nlrp3表达的恢复逆转了ClC-2下调对巨噬细胞脂质积累和炎症的影响。总体而言，我们的研究表明，ClC-2敲低可以通过抑制Nlrp3炎性体的活化来改善ox-LDL诱导的巨噬细胞泡沫细胞的形成和炎症。