A novel PINK1- and PARK2-dependent protective neuroimmune pathway in lethal sepsis

<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>