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

• Published in: The Journal of infectious diseases 2021-03, Vol.223 (6), p.1093-1102
• Main Authors: Wu, Zhenyu, Tian, Yuzi, Alam, Hasan B, Li, Patrick, Duan, Xiuzhen, Williams, Aaron M, Liu, Baoling, Ma, Jianjie, Li, Yongqing
• Format: Article
• Language: English
• Subjects: Animals; Bacteria; Bone marrow; Caspase 1; Flow cytometry; Immunocompromised hosts; Inoculation; Lethality; Macrophages; Mice; Mice, Knockout; Pneumonia; Pneumonia, Bacterial - enzymology; Protein-arginine deiminase; Protein-Arginine Deiminase Type 2 - metabolism; Protein-Arginine Deiminase Type 4; Pseudomonas aeruginosa; Sepsis; Sepsis - complications; Sepsis - microbiology
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiaa475

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 (2.5 × 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. 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. Pad2  −/− mice exhibited improved survival, attenuated lung injury, and enhanced bacterial clearance during Pseudomonas aeruginosa pneumonia-induced sepsis. The protective effects are probably associated with the regulatory effects of PAD2 on caspase-1-dependent pyroptosis.