Novel role for caspase 1 inhibitor VX765 in suppressing NLRP3 inflammasome assembly and atherosclerosis via promoting mitophagy and efferocytosis.
Ying JinYao LiuLei XuJie XuYulian XiongYazhi PengKe DingShuang ZhengNan YangZemei ZhangLin LiLiguo TanHongXian SongJian FuPublished in: Cell death & disease (2022)
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.
Keyphrases
- nlrp inflammasome
- cardiovascular disease
- cell death
- oxidative stress
- induced apoptosis
- mitochondrial dna
- signaling pathway
- copy number
- type diabetes
- dna damage
- cognitive decline
- transcription factor
- cardiovascular risk factors
- gene expression
- metabolic syndrome
- cardiovascular events
- skeletal muscle
- radiation therapy
- single cell
- dna methylation
- mouse model
- bone marrow
- coronary artery disease
- radiation induced
- insulin resistance
- mild cognitive impairment
- smoking cessation
- protein kinase