title: The E3 Ubiquitin Ligase c-Cbl Inhibits Microglia-Mediated CNS Inflammation by Regulating PI3K/Akt/NF-κB Pathway.
abstract: Microglia-mediated inflammation may play an important role in the pathophysiology progression of neurodegenerative diseases, such as Parkinson's disease (PD), but the molecular mechanisms are poorly understood.
  
  
  
  This study sought to determine whether E3 ubiquitin ligase c-Cbl plays a role in the brain inflammation and to explore the relevant molecular mechanism.
  
  
  
  After BV2 microglial cells and c-Cbl-deficient mice were treated with lipopolysaccharide (LPS), neuroinflammation and microglial activation were evaluated by immunohistochemistry, ELISA and Western blot. We further investigated the possible mechanism of c-Cbl in regulating microglial activation.
  
  
  
  Here, we showed that the E3 ubiquitin ligase c-Cbl had high expression in brain tissues including substantia nigra pars compacta (SNc), striatum and hippocampus, and it was abundantly expressed in microglia. Systemic LPS administration resulted in more severe microglial activation in CNS and increased expression of brain proinflammatory factors (TNF-α, IL-6, IL-1β and MCP-1) in c-Cbl knockout mice than wild type mice (WT). Downregulation of c-Cbl expression with c-Cbl siRNA in BV-2 microglial cells demonstrated a more robust increase in the proinflammatory factors release and NF-κB p65 nuclear translocation than that in control siRNA. Interestingly, Akt phosphorylation induced by LPS was also significantly augmented after c-Cbl knockdown. Moreover, blockade of PI3K/Akt activation by LY294002 significantly reduced inflammation response and NF-κB p65 nuclear translocation.
  
  
  
  In sum, c-Cbl inhibits expression of LPS-stimulated proinflammatory cytokines and chemokines in microglia. We demonstrate an unprecedented role for c-Cbl in microglia-mediated neuroinflammation involving PI3K/Akt/NF-κB pathway.
authors.affiliation: Department of Neurobiology, Capital Medical University, Beijing, China.|Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, China.|Beijing Institute for Brain Disorders, Beijing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Dong
authors.affiliation: The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Yu-Zhen
authors.initials: YZ
authors.lastname: Li
authors.affiliation: Department of Neurobiology, Capital Medical University, Beijing, China.|Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, China.|Beijing Institute for Brain Disorders, Beijing, China.
authors.forename: Hai-Ting
authors.initials: HT
authors.lastname: An
authors.affiliation: Department of Neurobiology, Capital Medical University, Beijing, China.|Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, China.|Beijing Institute for Brain Disorders, Beijing, China.
authors.forename: Ya-Long
authors.initials: YL
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Capital Medical University, Beijing, China.|Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, China.|Beijing Institute for Brain Disorders, Beijing, China.
authors.forename: Shi-Hao
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Department of Neurobiology, Capital Medical University, Beijing, China.|Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, China.|Beijing Institute for Brain Disorders, Beijing, China.
authors.forename: Yan-Jing
authors.initials: YJ
authors.lastname: Qian
authors.affiliation: Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, China.|Beijing Institute for Brain Disorders, Beijing, China.|Department of Physiology, Capital Medical University, Beijing, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Capital Medical University, Beijing, China.|Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, China.|Beijing Institute for Brain Disorders, Beijing, China.
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Zhen
authors.affiliation: Department of Pharmacology, Capital Medical University, Beijing, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, China.|Beijing Institute for Brain Disorders, Beijing, China.|Department of Physiology, Capital Medical University, Beijing, China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Gong
authors.affiliation: Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, China.|Beijing Institute for Brain Disorders, Beijing, China.|Department of Physiology, Capital Medical University, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Neurobiology, Capital Medical University, Beijing, China.|Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, China.|Beijing Institute for Brain Disorders, Beijing, China.
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Wang
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009573:Nitrites; D034741:RNA, Small Interfering; D050721:Proto-Oncogene Proteins c-cbl; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C493849:Cbl protein, mouse
keywords: Inflammation; Microglia; NF-κB; PI3K/Akt; c-Cbl