10.6084/m9.figshare.4039920.v2 Rui Kang Rui Kang Ling Zeng Ling Zeng Yangchun Xie Yangchun Xie Zhengwen Yan Zhengwen Yan Borong Zhou Borong Zhou Lizhi Cao Lizhi Cao Daniel J. Klionsky Daniel J. Klionsky Kevin J. Tracey Kevin J. Tracey Jianhua Li Jianhua Li Haichao Wang Haichao Wang Timothy R. Billiar Timothy R. Billiar Jianxin Jiang Jianxin Jiang Daolin Tang Daolin Tang A novel PINK1- and PARK2-dependent protective neuroimmune pathway in lethal sepsis Taylor & Francis Group 2016 HMGB1 hypoxia IL1A inflammasome mitophagy PARK2 PINK1 sepsis 2016-11-07 20:18:50 Journal contribution https://tandf.figshare.com/articles/journal_contribution/A_Novel_PINK1-_and_PARK2-dependent_Protective_Neuroimmune_Pathway_in_Lethal_Sepsis/4039920 <p>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 <i>pink1</i><sup>−/−</sup> and <i>park2</i><sup>−/−</sup> mice are more sensitive to polymicrobial sepsis-induced multiple organ failure and death. The decrease in the circulating level of the neurotransmitter dopamine in <i>pink1</i><sup>−/−</sup> and <i>park2</i><sup>−/−</sup> mice accelerates the release of a late sepsis mediator, HMGB1, via HIF1A-dependent anaerobic glycolysis and subsequent NLRP3-dependent inflammasome activation. Genetic depletion of <i>Nlrp3 or Hif1a</i> in <i>pink1</i><sup>−/−</sup> and <i>park2</i><sup>−/−</sup> 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 <i>pink1</i><sup>−/−</sup> and <i>park2</i><sup>−/−</sup> mice. The mRNA expression of <i>HIF1A</i> and <i>NLRP3</i> is upregulated, whereas the mRNA expression of <i>PINK1</i> and <i>PARK2</i> 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.</p>