Immunomodulation of the NLRP3 Inflammasome in Atherosclerosis, Coronary Artery Disease, and Acute Myocardial Infarction

Max J M Silvis, Evelyne J Demkes, Aernoud T L Fiolet, Mirthe Dekker, Lena Bosch, Gerardus P J van Hout, Leo Timmers, Dominique P V de Kleijn, Max J M Silvis, Evelyne J Demkes, Aernoud T L Fiolet, Mirthe Dekker, Lena Bosch, Gerardus P J van Hout, Leo Timmers, Dominique P V de Kleijn

Abstract

Cardiovascular disease (CVD) remains the leading cause of mortality and morbidity worldwide. Atherosclerosis is responsible for the majority of cardiovascular disorders with inflammation as one of its driving processes. The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, responsible for the release of the pro-inflammatory cytokines, interleukin-1β (IL-1β), and interleukin-18 (IL-18), has been studied extensively and showed to play a pivotal role in the progression of atherosclerosis, coronary artery disease (CAD), and myocardial ischemia reperfusion (I/R) injury. Both the NLRP3 inflammasome and its downstream cytokines, IL-1ß and IL-18, could therefore be promising targets in cardiovascular disease. This review summarizes the role of the NLRP3 inflammasome in atherosclerosis, CAD, and myocardial I/R injury. Furthermore, the current therapeutic approaches targeting the NLRP3 inflammasome and its downstream signaling cascade in atherosclerosis, CAD, and myocardial I/R injury are discussed.

Trial registration: ClinicalTrials.gov NCT01906749 NCT03048825 NCT01950299.

Keywords: Atherosclerosis; Coronary artery disease; Interleukin-18; Interleukin-1β; Ischemia-reperfusion injury; Myocardial infarction; NLRP3 inflammasome.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
NLRP3 inflammasome components. The NLRP3 inflammasome consist of three components: NLRP3, ASC, and caspase-1. NLRP3 protein contains three domains: NACHT, a central nucleotide domain; LRR, C-terminal leucine-rich repeats; and PYD, pyrin domain. ASC contains two interaction domains: pyrin domain (PYD) and caspase-recruitment domain (CARD). Caspase-1 contains a CARD and catalytic domain. Figure was created with Biorender.com
Fig. 2
Fig. 2
Inflammasome activation in atherosclerosis requires two steps; priming and activation. PRRs, such as TLRs, get stimulated by PAMPS & DAMPS leading to upregulation of the inflammasome components. Signals present in the atherosclerotic lesions (cholesterol crystals and oxidized LDL, disturbed flow) lead to activation of the inflammasome (activation). The NLRP3 inflammasome activates caspase-1 that in turn is responsible for the activation of interleukin-1β (IL-1β) and interleukin-18 (IL-18). Figure was created with Biorender.com
Fig. 3
Fig. 3
Central illustration: the NLRP3 inflammasome plays a dual role in coronary artery disease. (1) Progression of atherosclerosis. (2) Myocardial ischemia/reperfusion injury. Figure was created with Biorender.com

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