2. Academic Validation
  3. NLRP3 selectively drives IL-1β secretion by Pseudomonas aeruginosa infected neutrophils and regulates corneal disease severity

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

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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