Critical Role for the NLRP3 Inflammasome in Mediating IL-1β Production in Shigella sonnei -Infected Macrophages.

Shigellais one of the leading bacterial causes of diarrhea worldwide, affecting more than 165 million people annually. Among the serotypes ofShigella, Shigella sonneiis physiologically unique and endemic in human immunodeficiency virus-infected men who have sex with men. The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, a protein complex composed of NLRP3, apoptosis-associated speck-like protein, and caspase-1, recognizes, and responds to pathogen infection and diverse sterile host-derived or environmental danger signals to induce IL-1 beta and IL-18 production. Although theShigella flexneri-mediated activation of the NLRP3 inflammasome has been reported, the effect ofS. sonneion NLRP3 inflammasome activation remains unclear. We found thatS. sonneiinduced IL-1 beta production through NLRP3-dependent pathways in lipopolysaccharide-primed macrophages. A mechanistic study revealed thatS. sonneiinduced IL-1 beta production through P(2)X(7)receptor-mediated potassium efflux, reactive oxygen species generation, lysosomal acidification, and mitochondrial damage. In addition, the phagocytosis of viableS. sonneiwas important for IL-1 beta production. Furthermore, we demonstrated that NLRP3 negatively regulated phagocytosis and the bactericidal activity of macrophages againstS. sonnei. These findings provide mechanistic insight into the activation of the NLRP3 inflammasome byS. sonneiin macrophages.