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 ag

SUBMITTER: Kang R 

PROVIDER: S-EPMC5173260 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature