title: A novel PINK1- and PARK2-dependent protective neuroimmune pathway in lethal sepsis.
abstract: Although the PINK1-PARK2 pathway contributes to the pathogenesis of Parkinson disease, its roles in sepsis (a major challenge for critical care) were previously unknown. Here, we show that pink1-/-and park2-/-mice are more sensitive to polymicrobial sepsis-induced multiple organ failure and death. The decrease in the circulating level of the neurotransmitter dopamine in pink1-/-and park2-/-mice accelerates the release of a late sepsis mediator, HMGB1, via HIF1A-dependent anaerobic glycolysis and subsequent NLRP3-dependent inflammasome activation. Genetic depletion of Nlrp3 or Hif1a in pink1-/-and park2-/-mice confers protection against lethal polymicrobial sepsis. Moreover, pharmacological administration of dopamine agonist (e.g., pramipexole), HMGB1-inhibitor (e.g., neutralizing antibody or glycyrrhizin), or NLRP3-inhibitor (e.g., MCC950) reduces septic death in pink1-/-and park2-/-mice. The mRNA expression of HIF1A and NLRP3 is upregulated, whereas the mRNA expression of PINK1 and PARK2 is downregulated in peripheral blood mononuclear cells of patients with sepsis. Thus, an impaired PINK1-PARK2-mediated neuroimmunology pathway contributes to septic death and may represent a novel therapeutic target in critical care medicine.
authors.affiliation: a Department of Surgery , University of Pittsburgh , Pittsburgh , PA , USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.affiliation: a Department of Surgery , University of Pittsburgh , Pittsburgh , PA , USA.|b State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research institute for Traffic Medicine of People's Liberation Army, Daping Hospital, Third Military Medical University , Chongqing , China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zeng
authors.affiliation: a Department of Surgery , University of Pittsburgh , Pittsburgh , PA , USA.
authors.forename: Yangchun
authors.initials: Y
authors.lastname: Xie
authors.affiliation: a Department of Surgery , University of Pittsburgh , Pittsburgh , PA , USA.|c Department of Neurology , Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou, Guangdong , China.
authors.forename: Zhengwen
authors.initials: Z
authors.lastname: Yan
authors.affiliation: d Department of Neurology.|e Centre of DAMP Biology, Third Affiliated Hospital of Guangzhou Medical University , Guangzhou, Guangdong , China.
authors.forename: Borong
authors.initials: B
authors.lastname: Zhou
authors.affiliation: f Department of Pediatrics , Xiangya Hospital, Central South University , Changsha, Hunan , China.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Cao
authors.affiliation: g Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology , University of Michigan , Ann Arbor , MI , USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Klionsky
authors.affiliation: h Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research , Manhasset , NY , USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.affiliation: h Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research , Manhasset , NY , USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Li
authors.affiliation: h Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research , Manhasset , NY , USA.
authors.forename: Haichao
authors.initials: H
authors.lastname: Wang
authors.affiliation: a Department of Surgery , University of Pittsburgh , Pittsburgh , PA , USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: b State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research institute for Traffic Medicine of People's Liberation Army, Daping Hospital, Third Military Medical University , Chongqing , China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Jiang
authors.affiliation: a Department of Surgery , University of Pittsburgh , Pittsburgh , PA , USA.|e Centre of DAMP Biology, Third Affiliated Hospital of Guangzhou Medical University , Guangzhou, Guangdong , China.
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang
mesh_terms: D000332:Aerobiosis; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D006019:Glycolysis; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D009420:Nervous System / Q000201:enzymology* / Q000276:immunology*; D011494:Protein Kinases / Q000172:deficiency / Q000378:metabolism*; D018805:Sepsis / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D004298:Dopamine; D024243:HMGB1 Protein; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C492716:Nlrp3 protein, mouse; C111567:parkin protein
keywords: HMGB1; IL1A; PARK2; PINK1; hypoxia; inflammasome; mitophagy; sepsis