NLRP3 inflammasome: Its regulation and involvement in atherosclerosis

Abstract

Inflammasomes are intracellular complexes involved in the innate immunity that convert proIL-1β and proIL-18 to mature forms and initiate pyroptosis via cleaving procaspase-1. The most well-known inflammasome is NLRP3. Several studies have indicated a decisive and important role of NLRP3 inflammasome, IL-1β, IL-18, and pyroptosis in atherosclerosis. Modern hypotheses introduce atherosclerosis as an inflammatory/lipid-based disease and NLRP3 inflammasome has been considered as a link between lipid metabolism and inflammation because crystalline cholesterol and oxidized low-density lipoprotein (oxLDL) (two abundant components in atherosclerotic plaques) activate NLRP3 inflammasome. In addition, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and lysosome rupture, which are implicated in inflammasome activation, have been discussed as important events in atherosclerosis. In spite of these clues, some studies have reported that NLRP3 inflammasome has no significant effect in atherogenesis. Our review reveals that some molecules such as JNK-1 and ASK-1 (upstream regulators of inflammasome activation) can reduce atherosclerosis through inducing apoptosis in macrophages. Notably, NLRP3 inflammasome can also cause apoptosis in macrophages, suggesting that NLRP3 inflammasome may mediate JNK-induced apoptosis, and the apoptotic function of NLRP3 inflammasome may be a reason for the conflicting results reported. The present review shows that the role of NLRP3 in atherogenesis can be significant. Here, the molecular pathways of NLRP3 inflammasome activation and the implications of this activation in atherosclerosis are explained.

Rutaecarpine derivative R3 attenuates atherosclerosis via inhibiting NLRP3 inflammasome‐related inflammation and modulating cholesterol transport

“…Then, monocytes differentiate into macrophages that encounter an overabundance of modified lipid species, such as ox-LDL, and transform into lipid-laden foam cells. 38 Stimulation of the NLRP3 inflammasome and subsequent IL-1β release is related to the risk of coronary artery disease. 36 The NLRP3 inflammasome is involved in atherosclerosis 9,37 and is a link between inflammation and lipid metabolism in atherosclerosis.…”

Monocyte-Macrophages and T Cells in Atherosclerosis

“…Moreover, cholesterol accumulation in macrophages activates the inflammasome, leading to increased production of pro-atherogenic interleukin 1β. While cholesterol crystals have been implicated in this process (Duewell et al, 2010; Sheedy et al, 2013), other mechanisms likely contribute as well (Hoseini et al, 2017). …”

Caspase-1-associated immune activation in an accelerated SIV-infected rhesus macaque model

“…The NF-κB signaling pathway is an important upstream priming signal for activating caspase-1, possibly playing a crucial role for caspase-1 activation in the lymph nodes (Hoseini et al 2018). HIV infection can trigger immune cell NLRP3 inflammasome formation, caspase-1 activation, and NF-κB signaling (Chivero et al 2017; DeLuca et al 1999; Mayne et al 1998; Fiume et al 2012; Shah et al 2011; Liu et al 2014; Olivetta et al 2003; Varin et al 2003).…”