Inhibitors of the NLRP3 inflammasome pathway as promising therapeutic candidates for inflammatory diseases (Review)

Abstract

The inflammasome regulates innate immunity by serving as a signaling platform. The Nod-like receptor protein 3 (NLRP3) inflammasome, equipped with NLRP3, the adaptor protein apoptosis-associated speck-like protein (ASC) and pro-caspase-1, is by far the most extensively studied and well-characterized inflammasome. A variety of stimuli can activate the NLRP3 inflammasome. When activated, the NLRP3 protein recruits the adaptor ASC protein and activates pro-caspase-1, resulting in inflammatory cytokine maturation and secretion, which is associated with inflammation and pyroptosis. However, the aberrant activation of the NLRP3 inflammasome has been linked to various inflammatory diseases, including atherosclerosis, ischemic stroke, Alzheimer's disease, diabetes mellitus and inflammatory bowel disease. Therefore, the NLRP3 inflammasome has emerged as a promising therapeutic target for inflammatory diseases. In the present review, systematic searches were performed using 'NLRP3 inhibitor(s)' and 'inflammatory disease(s)' as key words. By browsing the literature from 2012 to 2022, 100 articles were retrieved, of which 35 were excluded as they were reviews, editorials, retracted or unavailable online, and 65 articles were included. According to the retrieved literature, the current understanding of NLRP3 inflammasome pathway activation in inflammatory diseases was summarize, and inhibitors of the NLRP3 inflammasome pathway targeting the NLRP3 protein and other inflammasome components or products were highlighted. Additionally, the present review briefly discusses the current novel efforts in clinical research.

Stroke Related Brain–Heart Crosstalk: Pathophysiology, Clinical Implications, and Underlying Mechanisms

“…[229] The NLRP3 (NLR pyrin domain-containing 3) inflammasome serves as a crucial component in the inflammatory response following stroke. [230] Lin et al discovered that the cardiac dysfunction induced by AIS is more severe in a type 2 diabetes mice model. Notably, they found that the NLRP3 inflammasome is primarily activated in M1 macrophages, and its inhibitor CY-09 can restore cardiac function.…”

Crosstalk of NLRP3 inflammasome and noncoding RNAs in cardiomyopathies

“…Recent articles have explored various approaches to modulate NLRP3 inflammasome activation. Small molecule inhibitors, for instance, MCC950 and CY‐09, have indicated promising results in attenuating NLRP3 inflammasome activation and subsequent cardiac damage in preclinical models 83 . Other investigations have assayed the role of dietary interventions, like omega‐3 fatty acids and flavonoids, in reducing NLRP3 inflammasome activity and mitigating cardiomyopathy progression.…”