Novel role for caspase 1 inhibitor VX765 in suppressing NLRP3 inflammasome assembly and atherosclerosis via promoting mitophagy and efferocytosis

Abstract

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.

The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4+T cell depletion, viral load and total HIV-1 DNA in HIV-1 infected humanized mice

“…Breaking out of this pathogenic cycle could represent an important building block to reduce non-AIDS related morbidities caused by persisting inflammation during cART (57). To date, despite increased therapeutic interests (45)(46)(47), no compound targeting the inflammasome was marketed (58). Nevertheless, The caspase 1 inhibitor VX-765 was approved by the Food and Drug Administration for human clinical trials, showed a good safety profile, and represents currently a promising drug to prevent the onset of inflammation in several diseases (47).…”

“…Altogether, these results strongly suggest that inflammasome activation occurs early during HIV-1 infection, and could be a central mechanism in the early viral escape to the immune system and furthermore, may facilitate the establishment of the pathogenic cycle of HIV-1 reservoirs persistence and inflammation. VX-765, a selective caspase 1 inhibitor, reduces activation and activity of caspase 1 and antagonize NLRP3 inflammasome assembly and activation in the context of several inflammatory disorders or diseases such as atheroschlerosis, sepsis, or alzheimer disease (45)(46)(47). Therefore, the aim of our study was to investigate the effects of the Caspase-1 inhibitor VX-765 in an humanized mouse model of HIV-1 infection as a therapeutic strategy to reduce HIV-1 induced inflammation and reservoirs establishment.…”

The emerging role of pyroptosis-related inflammasome pathway in atherosclerosis

“…Most recently, Li et al found that inhibition of nuclear factor kappa-B (NF-κB) phosphorylation and enhancement of ATP binding cassette subfamily A1 (ABCA1)-mediated cholesterol efflux can alleviate pyroptosis in ox-LDL-stimulated macrophages (Li et al 2022 ). Suppression of pyroptosis by VX-765, a specific caspase-1 inhibitor, increased cholesterol efflux and suppressed macrophage foam cell formation, suggesting the crosstalk between pyroptosis and cholesterol deposition through the NF-κB/ABCA1 pathway (Jin et al 2022 ). In addition to caspase-1, ox-LDL can also induce caspase-4/11-GSDMD-mediated pyroptosis and subsequent inflammation in macrophages, which is involved in the pathogenesis of AS (Jiang et al 2021 ).…”

“…Pyroptosis of VEC damages the endothelial function and promotes the release of pro-inflammatory cytokines, which stimulate the migration of monocytes to form early plaques (Libby et al 2019 ). Pyroptosis of macrophages further releases cytokines and induces foam cell formation (Jin et al 2022 ). Pyroptosis of VSMC reduces the size of the fibrous cap by decreasing collagen and matrix content, aggravating plaque instability and rupture.…”

The molecular mechanisms and intervention strategies of mitophagy in cardiorenal syndrome

“…And the functional role of mitophagy in different cell type of kidney and heart remains elusive. For example, promoting mitophagy in VSMCs accelerates atherosclerosis progression ( Kostin et al, 2003 ; He et al, 2019 ), whereas in endothelial cells and macrophages, promoting mitophagy exerts an atheroprotective role ( Li P. et al, 2020 ; Choi et al, 2021 ; Jin Y. et al, 2022 ). Besides, although enhanced mitophagy in rat ventricular myoblast cells (H9c2) has been demonstrated to provoke HF ( Huo et al, 2021 ), it has also been reported that the promotion of mitophagy in murine cardiac myocyte cell line (HL-1) prevents the development of HF.…”