Peptidylarginine Deiminases 2 Mediates Caspase-1-Associated Lethality in Pseudomonas aeruginosa Pneumonia-Induced Sepsis

Zhenyu Wu, Yuzi Tian, Hasan B. Alam, Patrick Li, Xiuzhen Duan, Aaron M. Williams, Baoling Liu, Jianjie Ma, Yongqing Li*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Background: Pseudomonas aeruginosa (PA) is a pathogenic bacterium that causes severe pneumonia in critically ill and immunocompromised patients. Peptidylarginine deiminase (PAD) 2, PAD4, and caspase-1 are important enzymes in mediating host response to infection. The goal of this study was to determine the interplay between PAD2, PAD4, and caspase-1 in PA pneumonia-induced sepsis. Methods: Pneumonia was produced in wild-type, Pad2-/-, and Pad4-/- mice by intranasal inoculation of PA (2.5â...×â...106 colony-forming units per mouse), and survival (nâ...=â...15/group) was monitored for 10 days. Bone marrow-derived macrophages (BMDMs) were isolated for in vitro studies. Samples were collected at specific timepoints for Western blot, bacterial load determination, and flow cytometry analysis. Results: Caspase-1-dependent inflammation was diminished in PA-inoculated Pad2-/- mice, contributing to reduced macrophage death and enhanced bacterial clearance. In addition, Pad2-/- mice exhibited improved survival and attenuated acute lung injury after PA infection. In contrast, Pad4-/- mice did not display diminished caspase-1 activation, altered bacterial loads, or improved survival. Conclusions: Peptidylarginine deiminase 2 plays an essential role in the pathogenesis of pulmonary sepsis by mediating caspase-1 activation. This goes against previous findings of PAD4 in sepsis. Our study suggests that PAD2 is a potential therapeutic target of PA pneumonia-induced sepsis.

Original languageEnglish (US)
Pages (from-to)1093-1102
Number of pages10
JournalJournal of Infectious Diseases
Volume223
Issue number6
DOIs
StatePublished - Mar 15 2021
Externally publishedYes

Keywords

  • Pseudomonas aeruginosa pneumonia
  • caspase-1
  • peptidylarginine deiminases 2 and 4
  • pyroptosis
  • sepsis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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