The NLRP3 Inflammasome as a Novel Therapeutic Target for Cardiac Fibrosis

Abstract

Cardiac fibrosis often has adverse cardiovascular effects, including heart failure, sudden death, and malignant arrhythmias. However, there is no targeted therapy for cardiac fibrosis. Inflammation is known to play a crucial role in the disorder, and the NLR pyrin domain-containing-3 (NLRP3) inflammasome is closely associated with innate immunity. Therefore, further understanding the pathophysiological role of the inflammasome in cardiac fibrosis may provide novel strategies for the prevention and treatment of the disorder. The aim of this review was to summarize the present knowledge of NLRP3 inflammasome-related mechanisms underlying cardiac fibrosis and to suggest potential targeted therapy that could be used to treat the condition.

Keywords: AIM2; ASC; NLRP3 inflammasome; cardiac fibrosis; caspase-1.

Figure 1

Regulation and function of NLRP3 inflammasome during cardiac fibrosis. (A) Caspase-1 activated by NLRP3 as well as caspase-4,5 and caspase-11 in the non-classical pathway are able to trigger pyroptosis. (B) Caspase-1 cleaves and activates pro-IL-1β and pro-IL-18, and is released extracellularly through the GSDMD pore. (C) The priming stage of NLRP3 inflammasome. (D) and (E) TGF-β/Smad is an important pathway leading to cardiac fibrosis and NLRP3 is capable of regulating it.

Figure 2

NLRP3 inflammasome activation in cardiovascular diseases to promote cardiac fibrosis. Under pathological conditions, such as myocardial infarction, hypertension, and hyperglycemia, atrial fibrillation, NLRP3 inflammasome in cardiomyocytes and fibroblasts are activated, collaboratively promoting the inflammatory cascade and pyroptosis. The resultant cardiac inflammation triggers myofibroblast activation and cardiac fibrosis.