Emerging Roles of Inflammasomes in Cardiovascular Diseases

Abstract

Cardiovascular diseases are known as the leading cause of morbidity and mortality worldwide. As an innate immune signaling complex, inflammasomes can be activated by various cardiovascular risk factors and regulate the activation of caspase-1 and the production and secretion of proinflammatory cytokines such as IL-1β and IL-18. Accumulating evidence supports that inflammasomes play a pivotal role in the progression of atherosclerosis, myocardial infarction, and heart failure. The best-known inflammasomes are NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes, among which NLRP3 inflammasome is the most widely studied in the immune response and disease development. This review focuses on the activation and regulation mechanism of inflammasomes, the role of inflammasomes in cardiovascular diseases, and the research progress of targeting NLRP3 inflammasome and IL-1β for related disease intervention.

Keywords: atherosclerosis; cardiac hypertrophy; heart failure; inflammasome; myocardial infarction.

Figure 1

Components and structure of inflammasomes. (A) The basic structure of most inflammasomes is based on the NOD-like receptor or ALR protein family as the sensor protein, ASC as the adaptor protein, and pro-caspase as the effector protein. Different sensor proteins consist of different domains: PYD, NACHT, LRR, function-to-find domains (FIIND), CARD, and HIN domain. (B) The PYD domain of NLRP3 or AIM2 interacts with the PYD domain of ASC, while the CARD domain of ASC can be combined with the CARD domain of the effector protein pro-caspase-1 to form inflammasome. NLRC4 does not contain the PYD domain but contains the CARD domain, which means that it can directly connect through the CARD domain with the CARD domain of the effector protein.

Figure 2

The activation of NLRP3 inflammasome and its role in cardiovascular diseases (CVDs). Inflammasome activation requires two independent steps: priming and triggering. Proinflammatory stimuli, such as PAMP, DAMP, or TNF, induce NF-κB signaling through TLR, TNF-R. The transcription factor NF-κB translocates to the nucleus and induces the expression of the IL-1β precursor pro-IL-1β and NLRP3. Cholesterol crystals or ox-LDL can be phagocytosed through receptor-mediated phagocytosis, leading to the formation of cholesterol crystals in phagolysosomes. Another mechanism of NLRP3 activation involves crystal-induced lysosomal rupture, or ATP-gated P2X7R-mediated decreased intracellular K⁺ concentration can activate NLRP3 protein. Once activated, NLRP3 recruits adapter molecule ASC, which interacts with pro-caspase-1, resulting in the formation of NLRP3 inflammasome. Active NLRP3 inflammasome promotes the recruitment and activation of caspase-1, which is responsible for the activation of IL-1β and IL-18 as well as the cleavage of GSDMD. The cleaved GSDMD then forms pores on the cell membrane, triggering pyroptosis. Most studies supported that the activation of NLRP3 inflammasome contributed to the development of atherosclerosis (AS), myocardial infarction (MI), myocardial ischemia/reperfusion (MI/R), and cardiac hypertrophy, which ultimately promoted heart failure.