Role of NLRP3 Inflammasomes in Atherosclerosis

Abstract

Inflammation with macrophage infiltration is a key feature of atherosclerosis. Although the mechanisms had been unclear, emerging evidence unveiled that NLRP3 inflammasomes, which regulate caspase-1 activation and subsequent processing of pro-IL-1β, trigger vascular wall inflammatory responses and lead to progression of atherosclerosis. NLRP3 inflammasomes are activated by various danger signals, such as cholesterol crystals, calcium phosphate crystals, and oxidized low-density lipoprotein in macrophages, to initiate inflammatory responses in the atherosclerotic lesion. Recent studies have further clarified the regulatory mechanisms and the potential therapeutic agents that target NLRP3 inflammasomes. In this study, we reviewed the present state of knowledge on the role of NLRP3 inflammasomes in the pathogenesis of atherosclerosis and discussed the therapeutic approaches that target NLRP3 inflammasomes.

Keywords: Cholesterol; Cytokines; Inflammation; Interleukin-1; Leukocytes.

Fig. 1.

Representative inflammasomes and their components Several PRRs that recognize distinct DAMPs form the inflammasome complex, which serves as the molecular platform to activate caspase-1. NLRP3 inflammasomes are composed of NLRP3, ASC, and caspase-1. NLRP3 binds ASC via PYD-PYD interaction. Subsequently, ASC binds caspase-1 via CARD–CARD interaction. NLRC4 inflammasomes are composed of NLRC4 and caspase-1, whereas AIM2 inflammasomes are composed of AIM2, ASC, and caspase-1. ATP, adenosine triphosphate; CARD, caspase recruitment domain; DAMPs, damage/danger-associated molecular patterns; HIN, hematopoietic interferon-inducible protein with a 200-amino-acid repeat; LRR, leucine-rich repeats; MSU, monosodium urate; NACHT, found in NAIP, CITA, HET-E ,and TP1; NLR, nucleotide-binding oligomerization domain-like receptor; PRRs, pattern recognition receptors; PYD, pyrin domain.

Fig. 2.

Mechanisms of NLRP3 inflammasome-driven IL-1β release IL-1β release is regulated in two-steps: Transcriptional synthesis of pro-IL-1β and proteolytic processing into its mature form by inflammasomes. The transcriptional regulation of IL-1β mRNA is mediated by TLRs and IL-1 receptor (signal 1), which also provides NLRP3 mRNA. Then, the NLRP3 inflammasome-activated caspase-1 processes accumulated pro-IL-1β and induces the release of IL-1β (signal 2). The common upstream pathways of NLRP3 inflammasomes include potassium efflux, generation of mitochondrial ROS, and lysosomal destabilization and leakage of cathepsin B. Activated caspase-1 also cleaves GSDMD, whose processed N-terminal fragment (GSDMD-N) increases plasma membrane permeability, resulting in pyroptosis. ROS, reactive oxygen species; TLRs, Toll-like receptors.

Fig. 3.

Proposed mechanism of NLRP3 inflammasome activation in atherosclerosis Cholesterol crystals are incorporated into the lysosome by phagocytosis or formed intracellularly when oxidized LDL is incorporated with CD36. Overloaded crystals cause lysosomal destabilization and rupture, which induce leakage of the lysosomal enzyme cathepsin B, resulting in the activation of NLRP3 inflammasomes. Calcium phosphate crystals also activate NLRP3 inflammasomes through a similar mechanism. LDL, low-density lipoprotein.