• Hajera Amatullah, Yuexin Shan, Brittany L Beauchamp, Patricia L Gali, Sahil Gupta, Tatiana Maron-Gutierrez, Edwin R Speck, Alison E Fox-Robichaud, Jennifer L Y Tsang, Shirley H J Mei, Tak W Mak, Patricia R M Rocco, John W Semple, Haibo Zhang, Pingzhao Hu, John C Marshall, Duncan J Stewart, Mary-Ellen Harper, Patricia C Liaw, W Conrad Liles, Claudia C Dos Santos, and Canadian Critical Care Translational Biology Group.
• 1 The Keenan Research Centre for Biomedical Science of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
• Am. J. Respir. Crit. Care Med. 2017 Apr 1; 195 (7): 889-905.

RationaleEffective and rapid bacterial clearance is a fundamental determinant of outcomes in sepsis. DJ-1 is a well-established reactive oxygen species (ROS) scavenger.ObjectivesBecause cellular ROS status is pivotal to inflammation and bacterial killing, we determined the role of DJ-1 in bacterial sepsis.MethodsWe used cell and murine models with gain- and loss-of-function experiments, plasma, and cells from patients with sepsis.Measurements And Main ResultsStimulation 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.ConclusionsThese novel findings reveal DJ-1 impairs optimal ROS production for bacterial killing with important implications for host survival in sepsis.

14 keywords...

hide…