PMID- 32729925
OWN - NLM
STAT- MEDLINE
DCOM- 20220210
LR  - 20220210
IS  - 1537-6613 (Electronic)
IS  - 0022-1899 (Linking)
VI  - 223
IP  - 6
DP  - 2021 Mar 29
TI  - Peptidylarginine Deiminases 2 Mediates Caspase-1-Associated Lethality in 
      Pseudomonas aeruginosa Pneumonia-Induced Sepsis.
PG  - 1093-1102
LID - 10.1093/infdis/jiaa475 [doi]
AB  - 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 x 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.
CI  - (c) The Author(s) 2020. Published by Oxford University Press for the Infectious 
      Diseases Society of America. All rights reserved. For permissions, e-mail: 
      journals.permissions@oup.com.
FAU - Wu, Zhenyu
AU  - Wu Z
AD  - Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan, USA.
AD  - Department of Infectious Diseases, Xiangya 2nd Hospital, Changsha, Hunan, China.
FAU - Tian, Yuzi
AU  - Tian Y
AD  - Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan, USA.
AD  - Department of Rheumatoid Diseases, Xiangya Hospital, Changsha, Hunan, China.
FAU - Alam, Hasan B
AU  - Alam HB
AD  - Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan, USA.
FAU - Li, Patrick
AU  - Li P
AD  - Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan, USA.
FAU - Duan, Xiuzhen
AU  - Duan X
AD  - Department of Pathology, Loyola University Medical Center, Maywood, Illinois, 
      USA.
FAU - Williams, Aaron M
AU  - Williams AM
AD  - Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan, USA.
FAU - Liu, Baoling
AU  - Liu B
AD  - Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan, USA.
FAU - Ma, Jianjie
AU  - Ma J
AD  - Department of Surgery, Division of Cardiac Surgery, The Ohio State University 
      Wexner Medical Center, Columbus, Ohio, USA.
FAU - Li, Yongqing
AU  - Li Y
AD  - Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Infect Dis
JT  - The Journal of infectious diseases
JID - 0413675
RN  - EC 3.4.22.36 (Caspase 1)
RN  - EC 3.5.3.15 (Protein-Arginine Deiminase Type 2)
RN  - EC 3.5.3.15 (Protein-Arginine Deiminase Type 4)
SB  - IM
MH  - Animals
MH  - *Caspase 1
MH  - Mice
MH  - Mice, Knockout
MH  - *Pneumonia, Bacterial/enzymology
MH  - Protein-Arginine Deiminase Type 2/*metabolism
MH  - Protein-Arginine Deiminase Type 4
MH  - Pseudomonas aeruginosa
MH  - *Sepsis/complications/microbiology
OTO - NOTNLM
OT  - Pseudomonas aeruginosa pneumonia
OT  - caspase-1
OT  - peptidylarginine deiminases 2 and 4
OT  - pyroptosis
OT  - sepsis
EDAT- 2020/07/31 06:00
MHDA- 2022/02/11 06:00
CRDT- 2020/07/31 06:00
PHST- 2020/06/15 00:00 [received]
PHST- 2020/07/24 00:00 [accepted]
PHST- 2020/07/31 06:00 [pubmed]
PHST- 2022/02/11 06:00 [medline]
PHST- 2020/07/31 06:00 [entrez]
AID - 5878917 [pii]
AID - 10.1093/infdis/jiaa475 [doi]
PST - ppublish
SO  - J Infect Dis. 2021 Mar 29;223(6):1093-1102. doi: 10.1093/infdis/jiaa475.