DJ-1/PARK7 Impairs Bacterial Clearance in Sepsis

Hajera Amatullah^{1

2}, Yuexin Shan¹, Brittany L Beauchamp³, Patricia L Gali¹, Sahil Gupta^{1

4}, Tatiana Maron-Gutierrez^{5

6}, Edwin R Speck¹, Alison E Fox-Robichaud⁷, Jennifer L Y Tsang^{1

8}, Shirley H J Mei⁹, Tak W Mak¹⁰, Patricia R M Rocco⁶, John W Semple¹, Haibo Zhang¹, Pingzhao Hu¹¹, John C Marshall¹, Duncan J Stewart⁹, Mary-Ellen Harper³, Patricia C Liaw⁸, W Conrad Liles¹², Claudia C Dos Santos^{1

4}; Canadian Critical Care Translational Biology Group

Affiliations

¹ 1 The Keenan Research Centre for Biomedical Science of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
² 2 Department of Physiology, Faculty of Medicine, and.
³ 4 Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
⁴ 3 Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, and.
⁵ 9 Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
⁶ 5 Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil.
⁷ 6 Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
⁸ 7 Thrombosis and Atherosclerosis Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
⁹ 8 Department of Medicine, McMaster University, Hamilton (Niagara Campus), Ontario, Canada.
¹⁰ 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.
¹¹ 11 Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and.
¹² 12 Department of Medicine, University of Washington, Seattle, Washington.

PMID: 27735193
DOI: 10.1164/rccm.201604-0730OC

DJ-1/PARK7 Impairs Bacterial Clearance in Sepsis

Hajera Amatullah et al. Am J Respir Crit Care Med. 2017.

. 2017 Apr 1;195(7):889-905.

doi: 10.1164/rccm.201604-0730OC.

Authors

Affiliations

¹ 1 The Keenan Research Centre for Biomedical Science of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
² 2 Department of Physiology, Faculty of Medicine, and.
³ 4 Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
⁴ 3 Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, and.
⁵ 9 Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
⁶ 5 Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil.
⁷ 6 Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
⁸ 7 Thrombosis and Atherosclerosis Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
⁹ 8 Department of Medicine, McMaster University, Hamilton (Niagara Campus), Ontario, Canada.
¹⁰ 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.
¹¹ 11 Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and.
¹² 12 Department of Medicine, University of Washington, Seattle, Washington.

PMID: 27735193
DOI: 10.1164/rccm.201604-0730OC

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 p47^phox, a critical component of the NADPH oxidase complex, disrupting the complex and facilitating Nox2 (gp91^phox) 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.

Keywords: DJ-1/PARK7; NADPH oxidase; bacterial clearance; reactive oxygen species; sepsis.

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Comment in

Maladaptive Suppression of Bacterial Clearance in Early Sepsis. Setting the Scene for Failure.
Waterer G, Restrepo MI. Waterer G, et al. Am J Respir Crit Care Med. 2017 Apr 1;195(7):846-847. doi: 10.1164/rccm.201610-1975ED. Am J Respir Crit Care Med. 2017. PMID: 28362200 No abstract available.

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DJ-1/PARK7 Impairs Bacterial Clearance in Sepsis

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DJ-1/PARK7 Impairs Bacterial Clearance in Sepsis

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