DJ-1/PARK7 Impairs bacterial clearance in sepsis
(2017) In American Journal of Respiratory and Critical Care Medicine 195(7). p.889-905- Abstract
Rationale: Effective and rapid bacterial clearance is a fundamental determinant of outcomes in sepsis. DJ-1 is a well-established reactive oxygen species (ROS) scavenger. Objectives: Because cellular ROS status is pivotal to inflammation and bacterial killing, we determined the role ofDJ-1 in bacterial sepsis. Methods: We used cell and murine models with gain- A nd loss-offunction experiments, plasma, and cells from patients with sepsis. Measurements and Main Results: Stimulation of bone marrow-derived macrophages (BMMs) with endotoxin resulted in increased DJ-1 mRNA and protein expression. Cellular and mitochondrial ROS was increased in DJ-1-deficient (-/-) BMMs compared with wild-type. In a clinically relevant model of... (More)
Rationale: Effective and rapid bacterial clearance is a fundamental determinant of outcomes in sepsis. DJ-1 is a well-established reactive oxygen species (ROS) scavenger. Objectives: Because cellular ROS status is pivotal to inflammation and bacterial killing, we determined the role ofDJ-1 in bacterial sepsis. Methods: We used cell and murine models with gain- A nd loss-offunction experiments, plasma, and cells from patients with sepsis. Measurements and Main Results: Stimulation of bone marrow-derived macrophages (BMMs) with endotoxin resulted in increased DJ-1 mRNA and protein expression. Cellular and mitochondrial ROS was increased in DJ-1-deficient (-/-) BMMs compared with wild-type. In a clinically relevant model of polymicrobial sepsis (cecal ligation and puncture), DJ-1-/- mice had improved survival and bacterial clearance. DJ-1-/- macrophages exhibited enhanced phagocytosis and bactericidal activity in vitro, and adoptive transfer of DJ-1-/- bonemarrow-derivedmononuclear cells rescued wild-type mice from cecal ligation and puncture-induced mortality. In stimulated BMMs, DJ-1 inhibited ROS production by binding to p47phox, a critical component of theNADPHoxidase complex, disrupting the complex and facilitating Nox2 (gp91phox) ubiquitination and degradation. Knocking downDJ-1 (siRNA) in THP-1 (human monocytic cell line) and polymorphonuclear cells from patients with sepsis enhanced bacterial killing and respiratory burst.DJ-1 protein levels were elevated in plasma from patients with sepsis. Higher levels of circulating DJ-1 were associated with increased organ failure and death. Conclusions: These novel findings reveal DJ-1 impairs optimalROS production for bacterial killing with important implications for host survival in sepsis.
(Less)
- author
- publishing date
- 2017-04-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Bacterial Clearance, DJ-1/PARK7, NADPH oxidase, Reactive oxygen Species, Sepsis
- in
- American Journal of Respiratory and Critical Care Medicine
- volume
- 195
- issue
- 7
- pages
- 17 pages
- publisher
- American Thoracic Society
- external identifiers
-
- pmid:27735193
- scopus:85011816347
- ISSN
- 1073-449X
- DOI
- 10.1164/rccm.201604-0730OC
- language
- English
- LU publication?
- no
- id
- 77cd9345-5ef3-4f6d-858b-1aa5081d83e9
- date added to LUP
- 2019-12-03 10:15:44
- date last changed
- 2024-04-17 01:18:24
@article{77cd9345-5ef3-4f6d-858b-1aa5081d83e9,
abstract = {{<p>Rationale: Effective and rapid bacterial clearance is a fundamental determinant of outcomes in sepsis. DJ-1 is a well-established reactive oxygen species (ROS) scavenger. Objectives: Because cellular ROS status is pivotal to inflammation and bacterial killing, we determined the role ofDJ-1 in bacterial sepsis. Methods: We used cell and murine models with gain- A nd loss-offunction experiments, plasma, and cells from patients with sepsis. Measurements and Main Results: Stimulation of bone marrow-derived macrophages (BMMs) with endotoxin resulted in increased DJ-1 mRNA and protein expression. Cellular and mitochondrial ROS was increased in DJ-1-deficient (<sup>-/-</sup>) BMMs compared with wild-type. In a clinically relevant model of polymicrobial sepsis (cecal ligation and puncture), DJ-1<sup>-/-</sup> mice had improved survival and bacterial clearance. DJ-1<sup>-/-</sup> macrophages exhibited enhanced phagocytosis and bactericidal activity in vitro, and adoptive transfer of DJ-1<sup>-/-</sup> bonemarrow-derivedmononuclear cells rescued wild-type mice from cecal ligation and puncture-induced mortality. In stimulated BMMs, DJ-1 inhibited ROS production by binding to p47phox, a critical component of theNADPHoxidase complex, disrupting the complex and facilitating Nox2 (gp91phox) ubiquitination and degradation. Knocking downDJ-1 (siRNA) in THP-1 (human monocytic cell line) and polymorphonuclear cells from patients with sepsis enhanced bacterial killing and respiratory burst.DJ-1 protein levels were elevated in plasma from patients with sepsis. Higher levels of circulating DJ-1 were associated with increased organ failure and death. Conclusions: These novel findings reveal DJ-1 impairs optimalROS production for bacterial killing with important implications for host survival in sepsis.</p>}},
author = {{Amatullah, Hajera and Shan, Yuexin and Beauchamp, Brittany L. and Gali, Patricia L. and Gupta, Sahil and Maron-Gutierrez, Tatiana and Speck, Edwin R. and Fox-Robichaud, Alison E. and Tsang, Jennifer L.Y. and Mei, Shirley H.J. and Mak, Tak W. and Rocco, Patricia R.M. and Semple, John W. and Zhang, Haibo and Hu, Pingzhao and Marshal, John C. and Stewart, Duncan J. and Harper, Mary Ellen and Liaw, Patricia C. and Liles, W. Conrad and Dos Santos, Claudia C.}},
issn = {{1073-449X}},
keywords = {{Bacterial Clearance; DJ-1/PARK7; NADPH oxidase; Reactive oxygen Species; Sepsis}},
language = {{eng}},
month = {{04}},
number = {{7}},
pages = {{889--905}},
publisher = {{American Thoracic Society}},
series = {{American Journal of Respiratory and Critical Care Medicine}},
title = {{DJ-1/PARK7 Impairs bacterial clearance in sepsis}},
url = {{http://dx.doi.org/10.1164/rccm.201604-0730OC}},
doi = {{10.1164/rccm.201604-0730OC}},
volume = {{195}},
year = {{2017}},
}