title: Manganese exposure facilitates microglial JAK2-STAT3 signaling and consequent secretion of TNF-a and IL-1β to promote neuronal death.
abstract: Chronic manganese (Mn) exposure can lead to neuroinflammation and neurological deficit, which resemble idiopathic Parkinson's disease (IPD). However, the precise mechanisms underlying Mn exposure-induced neurotoxicity remain incompletely understood. Microglia can become hyperactivated and plays a vital role in neuroinflammation and consequent neurodegeneration in response to pro-inflammatory stimuli. In the present study, we found that HAPI microglial cells exhibited increased secretion of pro-inflammatory TNF-α and IL-1β following Mn exposure in dose- and time-dependent manners. In addition, we showed that Mn exposure could trigger the activation of JAK2/STAT3 signaling pathway in microglia. Notably, Mn-induced secretion of TNF-α and IL-1β was significantly attenuated by the treatment of JAK2 inhibitor. Finally, through incubating PC12 neuronal cells with Mn-treated microglial conditioned medium, we demonstrated that Mn-induced secretion of microglial TNF-α and IL-1β facilitated neuronal apoptosis. Thus, we speculate that Mn exposure might trigger JAK2-STAT3 signal pathway in microglia, leading to resultant neuroinflammation and neuronal loss.
authors.affiliation: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Encephalopathy, Traditional Chinese Medicine Hospital of Haian County Affiliated Hospital, Nanjing University of Chinese Medicine of Hanlin College, Nantong, Jiangsu 226600, People's Republic of China.
authors.forename: Qijun
authors.initials: Q
authors.lastname: Dai
authors.affiliation: Department of Encephalopathy, Traditional Chinese Medicine Hospital of Haian County Affiliated Hospital, Nanjing University of Chinese Medicine of Hanlin College, Nantong, Jiangsu 226600, People's Republic of China.
authors.forename: Peipei
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Department of Encephalopathy, Traditional Chinese Medicine Hospital of Haian County Affiliated Hospital, Nanjing University of Chinese Medicine of Hanlin College, Nantong, Jiangsu 226600, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Encephalopathy, Traditional Chinese Medicine Hospital of Haian County Affiliated Hospital, Nanjing University of Chinese Medicine of Hanlin College, Nantong, Jiangsu 226600, People's Republic of China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Dai
authors.affiliation: Department of Encephalopathy, Traditional Chinese Medicine Hospital of Haian County Affiliated Hospital, Nanjing University of Chinese Medicine of Hanlin College, Nantong, Jiangsu 226600, People's Republic of China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Department of Encephalopathy, Traditional Chinese Medicine Hospital of Haian County Affiliated Hospital, Nanjing University of Chinese Medicine of Hanlin College, Nantong, Jiangsu 226600, People's Republic of China.
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Encephalopathy, Traditional Chinese Medicine Hospital of Haian County Affiliated Hospital, Nanjing University of Chinese Medicine of Hanlin College, Nantong, Jiangsu 226600, People's Republic of China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Encephalopathy, Traditional Chinese Medicine Hospital of Haian County Affiliated Hospital, Nanjing University of Chinese Medicine of Hanlin College, Nantong, Jiangsu 226600, People's Republic of China. Electronic address: qu_lianxia@163.com.
authors.forename: Lianxia
authors.initials: L
authors.lastname: Qu
authors.affiliation: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, Jiangsu 226001, People's Republic of China. Electronic address: jiang_junkang@163.com.
authors.forename: Junkang
authors.initials: J
authors.lastname: Jiang
mesh_terms: D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D004660:Encephalitis / Q000139:chemically induced*; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism*; D008297:Male; D008345:Manganese / Q000633:toxicity*; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D018836:Inflammation Mediators; D053583:Interleukin-1beta; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D014409:Tumor Necrosis Factor-alpha; D008345:Manganese; C507927:Jak2 protein, rat; D053614:Janus Kinase 2
keywords: Cytokines; JAK2/STAT3; Manganese; Microglia; Neuroinflammation