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- Title
DJ-1/PARK7 Impairs Bacterial Clearance in Sepsis.
- Authors
Amatullah, Hajera; Shan, Yuexin; Beauchamp, Brittany L.; Gali, Patricia L.; Gupta, Sahil; Maron-Gutierrez, Tatiana; Speck, Edwin R.; Fox-Robichaud, Alison E.; Tsang, Jennifer L. Y.; Mei, Shirley H. J.; Mak, Tak W.; Rocco, Patricia R. M.; Semple, John W.; Haibo Zhang; Pingzhao Hu; Marshall, John C.; Stewart, Duncan J.; Harper, Mary-Ellen; Liaw, Patricia C.; Liles, W. Conrad
- Abstract
<bold>Rationale: </bold>Effective and rapid bacterial clearance is a fundamental determinant of outcomes in sepsis. DJ-1 is a well-established reactive oxygen species (ROS) scavenger.<bold>Objectives: </bold>Because cellular ROS status is pivotal to inflammation and bacterial killing, we determined the role of DJ-1 in bacterial sepsis.<bold>Methods: </bold>We used cell and murine models with gain- and loss-of-function experiments, plasma, and cells from patients with sepsis.<bold>Measurements and Main Results: </bold>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-/- bone marrow-derived mononuclear 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 the NADPH oxidase complex, disrupting the complex and facilitating Nox2 (gp91phox) ubiquitination and degradation. Knocking down DJ-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.<bold>Conclusions: </bold>These novel findings reveal DJ-1 impairs optimal ROS production for bacterial killing with important implications for host survival in sepsis.
- Subjects
REACTIVE oxygen species; ANIMAL experimentation; BIOLOGICAL models; MICE; RESEARCH funding; SEPSIS
- Publication
American Journal of Respiratory & Critical Care Medicine, 2017, Vol 195, Issue 7, p889
- ISSN
1073-449X
- Publication type
journal article
- DOI
10.1164/rccm.201604-0730OC