title: CCL11 enhances excitotoxic neuronal death by producing reactive oxygen species in microglia.
abstract: The chemokine CCL11 (also known as eotaxin-1) is a potent eosinophil chemoattractant that mediates allergic diseases such as asthma, atopic dermatitis, and inflammatory bowel diseases. Previous studies demonstrated that concentrations of CCL11 are elevated in the sera and cerebrospinal fluids (CSF) of patients with neuroinflammatory disorders, including multiple sclerosis. Moreover, the levels of CCL11 in plasma and CSF increase with age, and CCL11 suppresses adult neurogenesis in the central nervous system (CNS), resulting in memory impairment. However, the precise source and function of CCL11 in the CNS are not fully understood. In this study, we found that activated astrocytes release CCL11, whereas microglia predominantly express the CCL11 receptor. CCL11 significantly promoted the migration of microglia, and induced microglial production of reactive oxygen species by upregulating nicotinamide adenine dinucleotide phosphate-oxidase 1 (NOX1), thereby promoting excitotoxic neuronal death. These effects were reversed by inhibition of NOX1. Our findings suggest that CCL11 released from activated astrocytes triggers oxidative stress via microglial NOX1 activation and potentiates glutamate-mediated neurotoxicity, which may be involved in the pathogenesis of various neurological disorders.
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Chikusa-Ku, Nagoya, Japan.
authors.forename: Bijay
authors.initials: B
authors.lastname: Parajuli
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Chikusa-Ku, Nagoya, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Horiuchi
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Chikusa-Ku, Nagoya, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mizuno
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Chikusa-Ku, Nagoya, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takeuchi
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Chikusa-Ku, Nagoya, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Suzumura
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology; D039481:CD11b Antigen / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D054413:Chemokine CCL11 / Q000378:metabolism*; D018920:Coculture Techniques; D004268:DNA-Binding Proteins; D018698:Glutamic Acid / Q000633:toxicity*; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D000074624:NADPH Oxidase 1; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D004268:DNA-Binding Proteins; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D018698:Glutamic Acid; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse
keywords: glia; glutamate; nicotinamide adenine dinucleotide phosphate-oxidase 1