Activation and regulation of NAIP/NLRC4 and NLRP3 inflammasomes during Salmonella infection: mechanisms and therapeutic implications.

Inflammasomes constitute a critical component of host defense against Salmonella infection, among which the NAIP/NLRC4 and NLRP3 complexes serve as the two principal signaling platforms. The NAIP/NLRC4 inflammasome functions as a rapid-response sensor that specifically recognizes bacterial flagellin and T3SS components, leading to caspase-1 activation, GSDMD-mediated pyroptosis, and IL-1β/IL-18 maturation. In contrast, NLRP3 integrates broad cellular stress signals, such as K⁺ efflux, mitochondrial ROS, and lysosomal damage, to amplify and sustain inflammatory responses, particularly at later stages of infection. This review synthesizes the current understanding of the structural basis, activation mechanisms, and spatiotemporal dynamics of these inflammasomes across immune and epithelial compartments. We further outline multilayered regulatory networks, including nuclear receptors, epigenetic regulators, post-translational modifications, non-coding RNAs, and autophagy-lysosome factors, that fine-tune inflammasome activity. Species-specific differences are emphasized, particularly the role of caspase-4/5 in human non-canonical signaling versus caspase-11 in mice. The functional interplay between NAIP/NLRC4 and NLRP3 is also examined, covering redundancy, cooperation, and potential antagonism. Finally, we discuss translational opportunities for targeting inflammasomes, including probiotics, postbiotics, and natural compounds, as antibiotic-sparing strategies in the context of antimicrobial resistance. Collectively, these insights delineate a multilayered host defense system and identify promising targets for immunomodulatory interventions against Salmonella.