The Laboratory of Inflammation and Vascular Biology, Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
Department of Ultrasound, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
Cell Death Dis. 2022 May 31;13(5):512. doi: 10.1038/s41419-022-04966-8.
Atherosclerosis is a maladaptive chronic inflammatory disease, which remains the leading cause of death worldwide. The NLRP3 inflammasome constitutes a major driver of atherosclerosis, yet the mechanism of action is poorly understood. Mitochondrial dysfunction is essential for NLRP3 inflammasome activation. However, whether activated NLRP3 inflammasome exacerbates mitochondrial dysfunction remains to be further elucidated. Herein, we sought to address these issues applying VX765, a well-established inhibitor of caspase 1. VX765 robustly restrains caspase 1-mediated interleukin-1β production and gasdermin D processing. Our study assigned VX765 a novel role in antagonizing NLRP3 inflammasome assembly and activation. VX765 mitigates mitochondrial damage induced by activated NLRP3 inflammasome, as evidenced by decreased mitochondrial ROS production and cytosolic release of mitochondrial DNA. VX765 blunts caspase 1-dependent cleavage and promotes mitochondrial recruitment and phosphorylation of Parkin, a key mitophagy regulator. Functionally, VX765 facilitates mitophagy, efferocytosis and M2 polarization of macrophages. It also impedes foam cell formation, migration and pyroptosis of macrophages. VX765 boosts autophagy, promotes efferocytosis, and alleviates vascular inflammation and atherosclerosis in both ApoE and Ldlr mice. However, these effects of VX765 were abrogated upon ablation of Nlrp3 in ApoE mice. This work provides mechanistic insights into NLRP3 inflammasome assembly and this inflammasome in dictating atherosclerosis. This study highlights that manipulation of caspase 1 paves a new avenue to treatment of atherosclerotic cardiovascular disease.
动脉粥样硬化是一种适应性慢性炎症性疾病，仍然是全球范围内主要的死亡原因。NLRP3 炎性体是动脉粥样硬化的主要驱动因素，但作用机制尚不清楚。线粒体功能障碍是 NLRP3 炎性体激活所必需的。然而，激活的 NLRP3 炎性体是否加剧线粒体功能障碍仍有待进一步阐明。在此，我们应用 caspase-1 的有效抑制剂 VX765 来解决这些问题。VX765 可强烈抑制 caspase-1 介导的白细胞介素-1β产生和 Gasdermin D 加工。我们的研究赋予了 VX765 拮抗 NLRP3 炎性体组装和激活的新作用。VX765 减轻了激活的 NLRP3 炎性体引起的线粒体损伤，表现为线粒体 ROS 产生减少和线粒体 DNA 从细胞质释放。VX765 抑制 caspase-1 依赖性裂解，并促进 Parkin 的募集和磷酸化，Parkin 是一种关键的线粒体自噬调节剂。功能上，VX765 促进了巨噬细胞的自噬、噬作用和 M2 极化。它还抑制了泡沫细胞的形成、巨噬细胞的迁移和细胞焦亡。VX765 增强了自噬，促进了噬作用，并缓解了 ApoE 和 Ldlr 小鼠的血管炎症和动脉粥样硬化。然而，在 ApoE 小鼠中敲除 Nlrp3 后，VX765 的这些作用被消除。这项工作为 NLRP3 炎性体组装和该炎性体在决定动脉粥样硬化中的作用提供了机制上的见解。本研究强调了操纵 caspase-1 为治疗动脉粥样硬化性心血管疾病开辟了新途径。
