NADPH oxidase-derived H2O2 mediates the regulatory effects of microglia on astrogliosis in experimental models of Parkinson's disease
Liyan Hou,
Xueying Zhou,
Cong Zhang,
Ke Wang,
Xiaofang Liu,
Yuning Che,
Fuqiang Sun,
Huihua Li,
Qingshan Wang,
Dan Zhang,
Jau-Shyong Hong
Affiliations
Liyan Hou
Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China
Xueying Zhou
Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China
Cong Zhang
Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China
Ke Wang
Department of Nutrition, Second Hospital, Dalian Medical University, Dalian 116023, China
Xiaofang Liu
Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China
Yuning Che
Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China
Fuqiang Sun
Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China
Huihua Li
Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China
Qingshan Wang
Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China; Corresponding author.
Dan Zhang
State Key Laboratory of Natural Products and Functions, Institute of Materia Medica, Chinese Academy of Medical Sciences ＆ Peking Union Medical College, Beijing 100050, China; Co-corresponding author.
Jau-Shyong Hong
Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
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 H2O2 through a process in which extracellularly generated H2O2 diffused 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 H2O2 is 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. Keywords: Parkinson's disease, NADPH oxidase, Microglia, Astrocyte, STATs, H2O2
