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

Author

Listed:
  • Martin S. Minns

    (University of California
    Odyssey Therapeutics)

  • Karl Liboro

    (University of California)

  • Tatiane S. Lima

    (University of California
    California State Polytechnic University)

  • 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)

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.

Suggested Citation

  • 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, 2023. "NLRP3 selectively drives IL-1β secretion by Pseudomonas aeruginosa infected neutrophils and regulates corneal disease severity," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41391-7
    DOI: 10.1038/s41467-023-41391-7
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    References listed on IDEAS

    as
    1. Mohamed F. Mohamed & Kajal Gupta & Josef W. Goldufsky & Ruchi Roy & Lauren T. Callaghan & Dawn M. Wetzel & Timothy M. Kuzel & Jochen Reiser & Sasha H. Shafikhani, 2022. "CrkII/Abl phosphorylation cascade is critical for NLRC4 inflammasome activity and is blocked by Pseudomonas aeruginosa ExoT," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
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