The NLRP3 inflammasome is a cytosolic sensor that mediates the maturation of pro-inflammatory cytokines IL-1β and IL-18. Chronic activation contributes to the pathogenesis of numerous noninfectious inflammatory diseases.
To summarize current evidence on NLRP3 activation pathways in chronic diseases and evaluate the contribution of gut dysbiosis in modulating this response.
Sustained NLRP3 activation is implicated in a broad range of diseases, including rheumatoid arthritis, systemic lupus erythematosus, type 2 diabetes, atherosclerosis, neurodegenerative disorders, atopic dermatitis, acne, fibromyalgia, and nonalcoholic fatty live disease (NAFLD) [1, 2, 3]. Activation is triggered by endogenous stress signals, including mitochondrial ROS, ATP, cholesterol crystals, and protein aggregates [4]. In genetic syndromes like cryopyrin-associated periodic syndrome, NLRP3 activation is constitutive and microbiota independent [5]. Recent studies are pointing toward a link between gut dysbiosis and NLRP3 activation in several of these diseases [6, 7, 8, 9]. Dysbiosis promotes systemic inflammation via increased intestinal permeability, reduced short-chain fatty acid production, and enhanced translocation of LPS and microbial metabolites [10]. These gut-derived signals prime or activate NLRP3 inflammasomes in distant tissues, including liver, adipose tissue, and brain.
NLRP3 acts as a convergence point for metabolic, microbial, and sterile inflammatory signals in chronic disease. Incorporating gut health into inflammasome-targeted strategies may enhance outcomes in inflammatory disease management.
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