NLRP3 selectively drives IL-1β secretion by Pseudomonas aeruginosa infected neutrophils and regulates corneal disease severity

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 and Eric Pearlman ()
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Martin S. Minns: University of California
Karl Liboro: University of California
Tatiane S. Lima: University of California
Serena Abbondante: University of California
Brandon A. Miller: Case Western Reserve University
Michaela E. Marshall: University of California
Jolynn Tran Chau: University of California
Alicia Roistacher: Case Western Reserve University
Arne Rietsch: Case Western Reserve University
George R. Dubyak: Case Western Reserve University
Eric Pearlman: University of California

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41391-7

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