Open AccessThe E3 Ubiquitin Ligase c‐Cbl Inhibits Microglia‐Mediated CNS Inflammation by Regulating PI 3K/Akt/ NF ‐ κ B Pathway
Author(s) -
Dong Lin,
Li YuZhen,
An HaiTing,
Wang YaLong,
Chen ShiHao,
Qian YanJing,
Wang Ke,
Zhen JunLi,
Fan Zheng,
Gong XiaoLi,
Zheng Yan,
Wang XiaoMin
Publication year - 2016
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12557
Subject(s) - proinflammatory cytokine , microglia , ubiquitin ligase , neuroinflammation , inflammation , protein kinase b , chemistry , chemokine , iκbα , phosphorylation , tumor necrosis factor alpha , downregulation and upregulation , microbiology and biotechnology , signal transduction , gene knockdown , nf κb , ubiquitin , biology , immunology , biochemistry , apoptosis , gene
Summary Background 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. Aims 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. Methods After BV 2 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. Results Here, we showed that the E3 ubiquitin ligase c‐Cbl had high expression in brain tissues including substantia nigra pars compacta ( SN c), 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 ‐1 β and MCP ‐1) in c‐Cbl knockout mice than wild type mice ( WT ). Downregulation of c‐Cbl expression with c‐Cbl si RNA in BV ‐2 microglial cells demonstrated a more robust increase in the proinflammatory factors release and NF ‐ κ B p65 nuclear translocation than that in control si RNA . Interestingly, Akt phosphorylation induced by LPS was also significantly augmented after c‐Cbl knockdown. Moreover, blockade of PI 3K/Akt activation by LY 294002 significantly reduced inflammation response and NF ‐ κ B p65 nuclear translocation. Conclusion 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 PI 3K/Akt/ NF ‐ κ B pathway.