title: NADPH oxidase-derived H2O2mediates the regulatory effects of microglia on astrogliosis in experimental models of Parkinson's disease.
abstract: Astrogliosis has long been recognized in Parkinson's disease (PD), the most common neurodegenerative movement disorder. However, the mechanisms of how astroglia become activated remain unclear. Reciprocal interactions between microglia and astroglia play a pivotal role in regulating the activities of astroglia. The purpose of this study is to investigate the mechanism by which microglia regulate astrogliosis by using lipopolysaccharide (LPS) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse PD models. We found that the activation of microglia preceded astroglia in the substantia nigra of mice treated with either LPS or MPTP. Furthermore, suppression of microglial activation by pharmacological inhibition or genetic deletion of NADPH oxidase (NOX2) in mice attenuated astrogliosis. The important role of NOX2 in microglial regulation of astrogliosis was further mirrored in a mixed-glia culture system. Mechanistically, H2O2, a product of microglial NOX2 activation, serves as a direct signal to regulate astrogliosis. Astrogliosis was induced by H2O2through a process in which extracellularly generated H2O2diffused into the cytoplasm and subsequently stimulated activation of transcription factors, STAT1 and STAT3. STAT1/3 activation regulated the immunological functions of H2O2-induced astrogliosis since AG490, an inhibitor of STAT1/3, attenuated the gene expressions of both proinflammatory and neurotrophic factors in H2O2-treated astrocyte. Our findings indicate that microglial NOX2-generated H2O2is able to regulate the immunological functions of astroglia via a STAT1/3-dependent manner, providing additional evidence for the immune pathogenesis and therapeutic studies of PD.
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Hou
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Nutrition, Second Hospital, Dalian Medical University, Dalian 116023, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China.
authors.forename: Yuning
authors.initials: Y
authors.lastname: Che
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China.
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China.
authors.forename: Huihua
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China. Electronic address: wangq4@126.com.
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Products and Functions, Institute of Materia Medica, Chinese Academy of Medical Sciences ＆ Peking Union Medical College, Beijing 100050, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
authors.forename: Jau-Shyong
authors.initials: JS
authors.lastname: Hong
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects; D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology* / Q000378:metabolism; D000074662:NADPH Oxidase 2 / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D006861:Hydrogen Peroxide; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2
keywords: Astrocyte; H(2)O(2); Microglia; NADPH oxidase; Parkinson's disease; STATs