title: Activation of Nur77 in microglia attenuates proinflammatory mediators production and protects dopaminergic neurons from inflammation-induced cell death.
abstract: Microglia-mediated neuroinflammation plays a critical role in the pathological development of Parkinson's disease (PD). Orphan nuclear receptor Nur77 (Nur77) is abundant in neurons, while its role in microglia-mediated neuroinflammation remains unclear. The present data demonstrated that the expression of Nur77 in microglia was reduced accompanied by microglia activation in response to lipopolysaccharide (LPS) in vitro and in experimental 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-PD mouse model. Nur77 over-expression or application of Nur77 agonist cytosporone B suppressed the expression of proinflammatory genes, such as inducible nitric oxide NOS, cyclooxygenase-2, IL-1β, and tumor necrosis factor-α in the activated microglia, while silenced Nur77 exaggerated the inflammatory responses in microglia. Moreover, activation of Nur77 suppressed the LPS-induced NF-κB activation which was partly dependent on p38 MAPK activity, since inhibition of p38 MAPK by SB203580 abolished the LPS-activated NF-κB in microglia. On the other hand, inhibition of p38 MAPK attenuated LPS-induced Nur77 reduction. Furthermore, in a microglia-conditioned cultured media system, Nur77 ameliorated the cytotoxicity to MN9D dopaminergic cells. Lastly, cytosporone B attenuated microglia activation and loss of dopaminergic neuron in the substantia nigra pars compacta (SNpc) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-PD mouse model. Taken together, these findings revealed the first evidence that Nur77 was an important modulator in microglia function that associated with microglia-mediated dopaminergic neurotoxicity, and thus modulation of Nur77 may represent a potential novel target for treatment for neurodegenerative disease.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.|College of Pharmaceutical Sciences and the Collaborative Innovation Center for Brain Science, Soochow University, Suzhou, China.
authors.forename: Tian-Ya
authors.initials: TY
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.|College of Pharmaceutical Sciences and the Collaborative Innovation Center for Brain Science, Soochow University, Suzhou, China.
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.|College of Pharmaceutical Sciences and the Collaborative Innovation Center for Brain Science, Soochow University, Suzhou, China.
authors.forename: Long-Tai
authors.initials: LT
authors.lastname: Zheng
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.|College of Pharmaceutical Sciences and the Collaborative Innovation Center for Brain Science, Soochow University, Suzhou, China.
authors.forename: Guang-Hui
authors.initials: GH
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.|College of Pharmaceutical Sciences and the Collaborative Innovation Center for Brain Science, Soochow University, Suzhou, China.
authors.forename: Xue-Chu
authors.initials: XC
authors.lastname: Zhen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020267:MPTP Poisoning / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*
chemical_list: D018836:Inflammation Mediators; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1
keywords: NF-κB; Nur77; Parkinson's disease; microglia; neuroinflammation; p38 mitogen-activated protein kinase