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

  • Nat Commun. 2023 Sep 20;14(1):5832. doi: 10.1038/s41467-023-41391-7.
Martin S Minns  #  1  2 ,  Karl Liboro  #  1 ,  Tatiane S Lima  #  1  3 ,  Serena Abbondante  1 ,  Brandon A Miller  4 ,  Michaela E Marshall  1 ,  Jolynn Tran Chau  1 ,  Alicia Roistacher  5 ,  Arne Rietsch  5 ,  George R Dubyak  4 ,  Eric Pearlman  6
Affiliations
  • 1. Departments of Ophthalmology and Physiology & Biophysics, University of California, Irvine, CA, USA.
  • 2. Odyssey Therapeutics, Boston, MA, USA.
  • 3. Department of Biological Sciences, California State Polytechnic University, Pomona, CA, USA.
  • 4. Department of Physiology & Biophysics, Case Western Reserve University, Cleveland, OH, USA.
  • 5. Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH, USA.
  • 6. Departments of Ophthalmology and Physiology & Biophysics, University of California, Irvine, CA, USA. [email protected].
  • # Contributed equally.
PMID: 37730693 DOI: 10.1038/s41467-023-41391-7
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.

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