Significance: Inflammasomes are multimeric complexes that, as part of the innate immune response, sense a wide range of pathogenic and sterile stimuli. They consist of three components, namely a sensor protein, an adaptor, and procaspase-1, which once activated result in secretion of proinflammatory interleukin (IL)-1β and IL-18 and, eventually, in a gasdermin D-dependent lytic cell death called pyroptosis. Recent Advances: Since their discovery 20 years ago, the molecular mechanisms underlying the regulation of inflammasomes have been extensively studied. Oxidative stress appears as a major contributor to modulate inflammasomes, especially NLRP3 as well as NLRP1, NLRP6, and NLRC4. Growing evidence supports the idea that the positive feedback between redox imbalance and inflammasome-driven inflammation fuels an OxInflammatory state in a variety of human pathologies. Critical Issues: The current knowledge about the redox signaling pathways involved in inflammasomes activation and functions are here highlighted. In addition, we discuss the role of this complex molecular network interaction in the onset and progression of pathological conditions including neurological and metabolic diseases as well as skin disorders, also with an insight on COVID-19-related pathology. Finally, the therapeutic strategies able to mitigate the redox-mediated inflammasome activation with synthetic and natural compounds as well as by acting on inflammasome-related post-translational modifications and microRNAs are also addressed. Future Directions: Further investigations leading to a deeper understanding of the reciprocal interaction between inflammasomes and reactive oxygen species will help identify other molecular targets for modulating their hyperactivated state, and to design novel therapeutics for chronic OxInflammatory conditions. Antioxid. Redox Signal. 39, 744-770.
Keywords: NLRs inflammasomes; chemical and natural inhibitors; microRNAs; post-translational modifications; reactive oxygen species.