Deletion of Nlrp3 Augments Survival during Polymicrobial Sepsis by Decreasing Autophagy and Enhancing Phagocytosis [INFECTIOUS DISEASE AND HOST RESPONSE]

NLRP3 inflammasome is a critical player in innate immunity. Neutrophil recruitment to tissues and effective neutrophil function are critical innate immune mechanisms for bacterial clearance. However, the role of NLRP3 in neutrophil-dependent bacterial clearance in polymicrobial sepsis is unclear. In this study, we evaluated the role of NLRP3 in polymicrobial sepsis induced by cecal ligation and puncture (CLP). Our results showed protection from death in NLRP3-deficient (Nlrp3^–/–) and NLRP3 inhibitor–treated wild-type (C57BL/6) mice. Nlrp3^–/– and NLRP3 inhibitor–treated mice displayed lower bacterial load but no impairment in neutrophil recruitment to peritoneum. However, neutrophil depletion abrogated protection from death in Nlrp3^–/– mice in response to CLP. Intriguingly, following CLP, Nlrp3^–/– peritoneal cells (primarily neutrophils) demonstrate decreased autophagy, augmented phagocytosis, and enhanced scavenger receptor (macrophage receptor with collagenous structure) and mannose-binding leptin expression. These findings enhance our understanding of the critical role of NLRP3 in modulating autophagy and phagocytosis in neutrophils and suggest that therapies should be targeted to modulate autophagy and phagocytosis in neutrophils to control bacterial burden in tissues during CLP-induced polymicrobial sepsis.

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