title: DJ-1/PARK7 Impairs Bacterial Clearance in Sepsis.
abstract: Effective and rapid bacterial clearance is a fundamental determinant of outcomes in sepsis. DJ-1 is a well-established reactive oxygen species (ROS) scavenger.
  
  
  
  Because cellular ROS status is pivotal to inflammation and bacterial killing, we determined the role of DJ-1 in bacterial sepsis.
  
  
  
  We used cell and murine models with gain- and loss-of-function experiments, plasma, and cells from patients with sepsis.
  
  
  
  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.
  
  
  
  These novel findings reveal DJ-1 impairs optimal ROS production for bacterial killing with important implications for host survival in sepsis.
authors.affiliation: 1 The Keenan Research Centre for Biomedical Science of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.|2 Department of Physiology, Faculty of Medicine, and.
authors.forename: Hajera
authors.initials: H
authors.lastname: Amatullah
authors.affiliation: 1 The Keenan Research Centre for Biomedical Science of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Shan
authors.affiliation: 4 Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Beauchamp
authors.affiliation: 1 The Keenan Research Centre for Biomedical Science of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Gali
authors.affiliation: 1 The Keenan Research Centre for Biomedical Science of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.|3 Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, and.
authors.forename: Sahil
authors.initials: S
authors.lastname: Gupta
authors.affiliation: 9 Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.|5 Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Maron-Gutierrez
authors.affiliation: 1 The Keenan Research Centre for Biomedical Science of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Speck
authors.affiliation: 6 Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Alison E
authors.initials: AE
authors.lastname: Fox-Robichaud
authors.affiliation: 1 The Keenan Research Centre for Biomedical Science of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.|7 Thrombosis and Atherosclerosis Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Jennifer L Y
authors.initials: JL
authors.lastname: Tsang
authors.affiliation: 8 Department of Medicine, McMaster University, Hamilton (Niagara Campus), Ontario, Canada.
authors.forename: Shirley H J
authors.initials: SH
authors.lastname: Mei
authors.affiliation: 10 Department of Medical Biophysics and Immunology, The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: 5 Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil.
authors.forename: Patricia R M
authors.initials: PR
authors.lastname: Rocco
authors.affiliation: 1 The Keenan Research Centre for Biomedical Science of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: John W
authors.initials: JW
authors.lastname: Semple
authors.affiliation: 1 The Keenan Research Centre for Biomedical Science of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 11 Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and.
authors.forename: Pingzhao
authors.initials: P
authors.lastname: Hu
authors.affiliation: 1 The Keenan Research Centre for Biomedical Science of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: John C
authors.initials: JC
authors.lastname: Marshall
authors.affiliation: 8 Department of Medicine, McMaster University, Hamilton (Niagara Campus), Ontario, Canada.
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
authors.affiliation: 4 Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
authors.affiliation: 7 Thrombosis and Atherosclerosis Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Liaw
authors.affiliation: 12 Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.affiliation: 1 The Keenan Research Centre for Biomedical Science of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.|3 Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, and.
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Dos Santos
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D000071617:Protein Deglycase DJ-1 / Q000097:blood*; D017382:Reactive Oxygen Species / Q000097:blood; D018805:Sepsis / Q000097:blood*
chemical_list: D017382:Reactive Oxygen Species; D000071617:Protein Deglycase DJ-1
keywords: DJ-1/PARK7; NADPH oxidase; bacterial clearance; reactive oxygen species; sepsis