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- Title
Peptidylarginine Deiminases 2 Mediates Caspase-1-Associated Lethality in Pseudomonas aeruginosa Pneumonia-Induced Sepsis.
- Authors
Wu, Zhenyu; Tian, Yuzi; Alam, Hasan B; Li, Patrick; Duan, Xiuzhen; Williams, Aaron M; Liu, Baoling; Ma, Jianjie; Li, Yongqing
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>Pneumonia was produced in wild-type, Pad2-/-, and Pad4-/- mice by intranasal inoculation of PA (2.5 × 106 colony-forming units per mouse), and survival (n = 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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
PSEUDOMONAS aeruginosa; SEPSIS; PATHOGENIC bacteria; IMMUNOCOMPROMISED patients; FLOW cytometry
- Publication
Journal of Infectious Diseases, 2021, Vol 223, Issue 6, p1093
- ISSN
0022-1899
- Publication type
journal article
- DOI
10.1093/infdis/jiaa475