NLRP3 Deficiency Enhances Neutrophil Motility and Phagocytic Function in the Inflamed Kidney.

Abstract

Neutrophils serve host defense through phagocytic activity in acute kidney injury. However, excessive neutrophil activation drives tissue damage during systemic inflammation. NOD-like receptor family pyrin domain-containing 3 (NLRP3) has been reported to regulate neutrophil function in inflammatory conditions, but it remains unclear how NLRP3 modulates neutrophil function in the kidney. We investigated the role of NLRP3 in regulating neutrophil phagocytic activity and infiltration in the kidney. Nlrp3 knockout (KO) and Nlrp3 KO/lysozyme M-GFP mice were analyzed by time-lapse imaging and intravital imaging under naïve and LPS-treated conditions. Nlrp3 KO neutrophils exhibited enhanced motility and phagocytic activity against pHrodo⁺ Escherichia coli particles. The enhanced phagocytic activity was confirmed at both cellular and tissue levels in Nlrp3 deficient kidneys in vivo. Nlrp3 deficient kidneys showed increased neutrophil infiltration accompanied by upregulation of Cxcl2 and Cxcr2 and downregulation of Cxcl12 and Cxcr4 under naïve and LPS-treated conditions. Despite increased infiltration, Nlrp3 deficient kidneys under LPS treatment displayed reduced Il1b and Il6 expression and attenuated tissue damage. Collectively, these findings suggest that NLRP3 suppresses neutrophil effector function at the cellular level. At the tissue level, NLRP3 amplifies inflammatory tissue injury in the kidney.