DJ-1/PARK7 Impairs Bacterial Clearance in Sepsis Academic Article uri icon

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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 of DJ-1 in bacterial sepsis. METHODS: We used cell and murine models with gain- and loss-of-function 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-/- 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. CONCLUSIONS: These novel findings reveal DJ-1 impairs optimal ROS production for bacterial killing with important implications for host survival in sepsis.

authors

  • Amatullah, Hajera
  • Shan, Yuexin
  • Beauchamp, Brittany L
  • Gali, Patricia L
  • Gupta, Sahil
  • Maron-Gutierrez, Tatiana
  • Speck, Edwin R
  • Fox-Robichaud, Alison
  • Tsang, Jennifer
  • Mei, Shirley HJ
  • Mak, Tak W
  • Rocco, Patricia RM
  • Semple, John W
  • Zhang, Haibo
  • Hu, Pingzhao
  • Marshall, John C
  • Stewart, Duncan J
  • Harper, Mary-Ellen
  • Liaw, Patricia Chia-Ying
  • Liles, W Conrad
  • dos Santos, Claudia C

publication date

  • April 2017