NLRP3 inflammasome and pyroptosis: implications in inflammation and multisystem disorders

Abstract

The NLRP3 inflammasome is a multiprotein complex that senses diverse pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), activating the pyroptosis pathway. Pyroptosis is a form of programmed cell death that plays a crucial role in immune responses and inflammatory processes. The NLRP3 inflammasome-gasdermin D (GSDMD) axis has emerged as a critical therapeutic target in inflammatory diseases. Oligomerization of NLRP3 triggers caspase-1 activation, which subsequently induces GSDMD palmitoylation—an essential event that facilitates pyroptosis. Clinically, NLRP3 inhibitors, such as MCC950, demonstrate protective effects in NLRP3-mediated inflammatory diseases. GSDMD holds substantial potential as a diagnostic, monitoring, and therapeutic target across diverse diseases, underscoring its utility as a pan-biomarker. This review aims to synthesize current knowledge regarding the structure and function of the NLRP3 inflammasome and the regulatory mechanisms governing pyroptosis. Additionally, integrating findings from multiple physiological systems highlights the key roles of the NLRP3 inflammasome and pyroptosis in disease pathogenesis, offering novel perspectives for targeting inflammatory responses and associated disorders.

Keywords

• Pyroptosis
• NLRP3 inflammasome
• NEK7
• Palmitoylation of GSDMD-NT
• Ninjurin-1
• Innate immunity