NLRP3 Inflammasome in Central Nervous System Infections: Mechanistic Conservation, Functional Duality, and Therapeutic Implications

The NLRP3 inflammasome is a central innate immune sensor that matures pro‑inflammatory cytokines and can drive neuroinflammation. Dysregulated activation contributes to tissue injury and neuronal damage. This review systematically examines pathogen-specific mechanisms of NLRP3 activation in central nervous system (CNS) infections caused by bacteria, viruses, parasites, and fungal pathogens. These pathogens engage markedly heterogeneous upstream triggers, most commonly lysosomal cathepsin B release, reactive oxygen species generation, and potassium efflux, alongside less broadly documented mechanisms including mitochondria-associated membrane signaling and direct pathogen–protein interactions. Despite this diversity, these pathways ultimately converge on a common downstream axis defined by caspase-1-dependent maturation of IL-1β and IL-18, followed by pyroptosis. Evidence is well substantiated for certain pathogens but remains largely inferential for others, and host-protective patterns of NLRP3 activity are distinguished from immunopathogenic ones. Finally, the therapeutic promise and translational challenges of NLRP3-targeted interventions in the infected CNS are evaluated, indicating that inhibition strategies must be tailored to the pathogen-specific context, as balancing antimicrobial defense against collateral neuronal injury remains a central challenge in this field.