title: Microglia-Derived Cytokines/Chemokines Are Involved in the Enhancement of LPS-Induced Loss of Nigrostriatal Dopaminergic Neurons in DJ-1 Knockout Mice.
abstract: Mutation of DJ-1 (PARK7) has been linked to the development of early-onset Parkinson's disease (PD). However, the underlying molecular mechanism is still unclear. This study is aimed to compare the sensitivity of nigrostriatal dopaminergic neurons to lipopolysaccharide (LPS) challenge between DJ-1 knockout (KO) and wild-type (WT) mice, and explore the underlying cellular and molecular mechanisms. Our results found that the basal levels of interferon (IFN)-γ (the hub cytokine) and interferon-inducible T-cell alpha chemoattractant (I-TAC) (a downstream mediator) were elevated in the substantia nigra of DJ-1 KO mice and in microglia cells with DJ-1 deficiency, and the release of cytokine/chemokine was greatly enhanced following LPS administration in the DJ-1 deficient conditions. In addition, direct intranigral LPS challenge caused a greater loss of nigrostriatal dopaminergic neurons and striatal dopamine content in DJ-1 KO mice than in WT mice. Furthermore, the sensitization of microglia cells to LPS challenge to release IFN-γ and I-TAC was via the enhancement of NF-κB signaling, which was antagonized by NF-κB inhibitors. LPS-induced increase in neuronal death in the neuron-glia co-culture was enhanced by DJ-1 deficiency in microglia, which was antagonized by the neutralizing antibodies against IFN-γ or I-TAC. These results indicate that DJ-1 deficiency sensitizes microglia cells to release IFN-γ and I-TAC and causes inflammatory damage to dopaminergic neurons. The interaction between the genetic defect (i.e. DJ-1) and inflammatory factors (e.g. LPS) may contribute to the development of PD.
authors.affiliation: Department of Life Science, College of Life Science, National Taiwan University, Taipei, Taiwan.|Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.|Drug Research Center, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Chien
authors.affiliation: Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Houng-Chi
authors.initials: HC
authors.lastname: Liou
authors.affiliation: Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.|Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Horng-Huei
authors.initials: HH
authors.lastname: Liou
authors.affiliation: Department of Life Science, College of Life Science, National Taiwan University, Taipei, Taiwan.|Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.|Drug Research Center, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Wen-Mei
authors.initials: WM
authors.lastname: Fu
mesh_terms: D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000502:physiology*; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016207:Cytokines / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D054464:Peroxiredoxins / Q000235:genetics / Q000502:physiology*; D000071617:Protein Deglycase DJ-1; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D015513:Oncogene Proteins; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D004298:Dopamine