A novel PINK1- and PARK2-dependent protective neuroimmune pathway in lethal sepsis
Rui Kang
Ling Zeng
Yangchun Xie
Zhengwen Yan
Borong Zhou
Lizhi Cao
Daniel J. Klionsky
Kevin J. Tracey
Jianhua Li
Haichao Wang
Timothy R. Billiar
Jianxin Jiang
Daolin Tang
10.6084/m9.figshare.4039920.v2
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>
2016-11-07 20:18:50
HMGB1
hypoxia
IL1A
inflammasome
mitophagy
PARK2
PINK1
sepsis