Department of Pathology, Anhui Armed Police General Hospital, Hefei, 230032, Anhui, China.
Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui, China.
Cell Biol Int. 2020 Jul;44(7):1481-1490. doi: 10.1002/cbin.11343. Epub 2020 Mar 27.
Pyroptosis is a form of cell death that is uniquely dependent on caspase-1. Pyroptosis involved in oxidized low-density lipoprotein (ox-LDL)-induced human macrophage death through the promotion of caspase-1 activation is important for the formation of unstable plaques in atherosclerosis. The mitochondrial outer membrane protein NIX directly interacts with microtubule-associated protein 1 light chain 3 (LC3). Although we previously showed that NIX-mediated mitochondrial autophagy is involved in the clearance of damaged mitochondria, how NIX contributes to ox-LDL-induced macrophage pyroptosis remains unknown. Here, immunoperoxidase staining Nix expression decreased in human atherosclerosis. When we silenced NIX expression in murine macrophage cell, active caspase-1, and mature interleukin-1β expression levels were increased and LC3 was reduced. In addition, LDH release and acridine orange and ethidium bromide staining indicated that damage to macrophage cell membranes induced by ox-LDL was substantially worse. Moreover, intracellular reactive oxygen species and NLRP3 inflammasome levels increased. Taken together, these results demonstrated that NIX inhibits ox-LDL-induced macrophage pyroptosis via autophagy in atherosclerosis.
细胞焦亡是一种依赖于半胱天冬酶-1（caspase-1）的细胞程序性死亡形式。细胞焦亡参与氧化型低密度脂蛋白（ox-LDL）诱导的人巨噬细胞死亡，通过促进半胱天冬酶-1 的激活，对动脉粥样硬化不稳定斑块的形成很重要。线粒体膜外蛋白 NIX 直接与微管相关蛋白 1 轻链 3（LC3）相互作用。虽然我们之前已经表明，NIX 介导的线粒体自噬参与了受损线粒体的清除，但 NIX 如何促进 ox-LDL 诱导的巨噬细胞细胞焦亡仍不清楚。本研究中，免疫过氧化物酶染色显示人动脉粥样硬化中 Nix 的表达减少。当我们在鼠源巨噬细胞中沉默 NIX 表达时，活性 caspase-1 和成熟的白细胞介素-1β表达水平增加，而 LC3 减少。此外，LDH 释放以及吖啶橙和溴化乙锭染色表明 ox-LDL 诱导的巨噬细胞膜损伤明显更严重。此外，细胞内活性氧和 NLRP3 炎性小体水平增加。综上所述，这些结果表明 NIX 通过自噬抑制动脉粥样硬化中 ox-LDL 诱导的巨噬细胞细胞焦亡。
