NLRP3 inflammasome: The rising star in cardiovascular diseases

Abstract

Cardiovascular diseases (CVDs) are the prevalent cause of mortality around the world. Activation of inflammasome contributes to the pathological progression of cardiovascular diseases, including atherosclerosis, abdominal aortic aneurysm, myocardial infarction, dilated cardiomyopathy, diabetic cardiomyopathy, heart failure, and calcific aortic valve disease. The nucleotide oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome plays a critical role in the innate immune response, requiring priming and activation signals to provoke the inflammation. Evidence shows that NLRP3 inflammasome not only boosts the cleavage and release of IL-1 family cytokines, but also leads to a distinct cell programmed death: pyroptosis. The significance of NLRP3 inflammasome in the CVDs-related inflammation has been extensively explored. In this review, we summarized current understandings of the function of NLRP3 inflammasome in CVDs and discussed possible therapeutic options targeting the NLRP3 inflammasome.

Keywords: NLRP3 inflammasome; cardiovascular diseases; inflammation; interleukins; pyroptosis.

Figure 1

The overall mechanism of the NLRP3 inflammasome activation. In the priming step, PAMPs, DAMPs, IL-1β and TNF induce the phosphorylation and lysis of inhibitor of NF-κB (IκB), activate the NF-κB pathway, leading to the transcription of NLRP3, pro-IL-1β and pro-IL-18. In the activation process, NLRP3 recruits ASC, which links to pro-caspase-1, to assembly the inflammasome. Then, NEK7 is attached to inflammasome and induces the oligomerization. The efflux of K+, influx of Na+ and Ca2+ (from extrecellular and endoplasmic reticulum), ROS, mtDNA and oxLDL or cholesterol crystal- induced lysosomal damage contribute to the assembly. The efflux of Cl- promotes the attachment of NEK7 and then the oligomerization. Caspase-1 is activated by autoproteolysis on oligomeric NLRP3 inflammasome, cleaving pro-IL-1 and pro-IL-18 into IL-1 and IL-18. Caspase-1 also cleaves GSDMD to form the GSDMD pore, leading to the release of IL-1 and pyroptosis. NLRP3, nucleotide oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain (PYD)-containing protein3; PAMP, pathogen- associated molecular patterns; DAMP, damage associated molecular patterns; TNF, tumor necrosis factor; NF-κB, nuclear factor κ-light-chain enhancer of activated B cells; ASC, apotosis-associated speck-like protein containing a CARD; NEK7, NIMA-related kinase 7; NIMA, never in mitosis gene A; ROS, reactive oxygen species; oxLDL, oxidized low-density lipoprotein; GSDMD, gasdermin D.

Figure 2

Pyroptosis and differentiation mediated by NLRP3 inflammasome result in various cardiovascular diseases. Atherosclerosis: The activation of NLRP3 happened in vascular endothelial cells leads to cell pyroptosis and subsequent lipid accumulation, which induces the formation of atherosclerotic plaque. Pericarditis: The activation of NLRP3 happened in pericardial endothelial cells can be initiated by pro-inflammatory substances, and also worsens the inflammatory development of pericarditis. Abdominal aortic aneurysm: Activation happened in aorta smooth muscle cells leads to cell loss, resulting in abdominal aortic aneurysm. Myocardial infarction and Stroke: Activation happened in reperfusion cells exacerbates ischemia-reperfusion injury, worsens the myocardial infarction or stroke symptom. Cardiomyopathy: Chronic NLRP3 inflammation triggered by hyperglycaemia or hyperlipidemia promotes pyroptosis of cardiocytes and remodeling of ventricular, ending in dilated or diabetic cardiomyopathy. Calcific aortic valve disease: NLRP3 inflammation in aortic valve can activate quiescent valve interstitial cells into activated valve interstitial cells, initiating the calcific process of valve. NLRP3, nucleotide oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain (PYD)-containing protein 3.