NLRP3 Selectively Drives IL-1β Secretion by Pseudomonas aeruginosa Infected Neutrophils and Regulates Corneal Disease Severity

Authors

Martin S Minns
Karl Liboro
Tatiane S Lima
Serena Abbondante
Brandon A Miller
Michaela E Marshall
Jolynn Tran Chau
Alicia Roistacher
Arne Rietsch
George R Dubyak
Eric Pearlman

Publication Date

9-20-2023

Journal

Nature Communications

Abstract

Macrophages infected with Gram-negative bacteria expressing Type III secretion system (T3SS) activate the NLRC4 inflammasome, resulting in Gasdermin D (GSDMD)-dependent, but GSDME independent IL-1β secretion and pyroptosis. Here we examine inflammasome signaling in neutrophils infected with Pseudomonas aeruginosa strain PAO1 that expresses the T3SS effectors ExoS and ExoT. IL-1β secretion by neutrophils requires the T3SS needle and translocon proteins and GSDMD. In macrophages, PAO1 and mutants lacking ExoS and ExoT (ΔexoST) require NLRC4 for IL-1β secretion. While IL-1β release from ΔexoST infected neutrophils is also NLRC4-dependent, infection with PAO1 is instead NLRP3-dependent and driven by the ADP ribosyl transferase activity of ExoS. Genetic and pharmacologic approaches using MCC950 reveal that NLRP3 is also essential for bacterial killing and disease severity in a murine model of P. aeruginosa corneal infection (keratitis). Overall, these findings reveal a function for ExoS ADPRT in regulating inflammasome subtype usage in neutrophils versus macrophages and an unexpected role for NLRP3 in P. aeruginosa keratitis.

Keywords

Animals, Mice, Corneal Diseases, Inflammasomes, Neutrophils, NLR Family, Pyrin Domain-Containing 3 Protein, Patient Acuity, Pseudomonas aeruginosa

Comments

Supplementary Materials

PMID: 37730693