title: Methionine sulfoxide reductase A negatively controls microglia-mediated neuroinflammation via inhibiting ROS/MAPKs/NF-κB signaling pathways through a catalytic antioxidant function.
abstract: OBJECTIVE
  Oxidative burst is one of the earliest biochemical events in the inflammatory activation of microglia. Here, we investigated the potential role of methionine sulfoxide reductase A (MsrA), a key antioxidant enzyme, in the control of microglia-mediated neuroinflammation.
  
  
  RESULTS
  MsrA was detected in rat microglia and its expression was upregulated on microglial activation. Silencing of MsrA exacerbated lipopolysaccharide (LPS)-induced activation of microglia and the production of inflammatory markers, indicating that MsrA may function as an endogenous protective mechanism for limiting uncontrolled neuroinflammation. Application of exogenous MsrA by transducing Tat-rMsrA fusion protein into microglia attenuated LPS-induced neuroinflammatory events, which was indicated by an increased Iba1 (a specific microglial marker) expression and the secretion of pro-inflammatory cytokines, and this attenuation was accompanied by inhibiting multiple signaling pathways such as p38 and ERK mitogen-activated protein kinases (MAPKs) and nuclear factor kappaB (NF-κB). These effects were due to MsrA-mediated reactive oxygen species (ROS) elimination, which may be derived from a catalytic effect of MsrA on the reaction of methionine with ROS. Furthermore, the transduction of Tat-rMsrA fusion protein suppressed the activation of microglia and the expression of pro-inflammatory factors in a rat model of neuroinflammation in vivo.
  
  
  METHODS
  This study provides the first direct evidence for the biological significance of MsrA in microglia-mediated neuroinflammation.
  
  
  CONCLUSIONS
  Our data provide a profound insight into the role of endogenous antioxidative defense systems such as MsrA in the control of microglial function.
authors.affiliation: 1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology , Wuhan City, China .
authors.forename: Hua
authors.initials: H
authors.lastname: Fan
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Wu
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Zhuang-Li
authors.initials: ZL
authors.lastname: Hu
authors.forename: Wen
authors.initials: W
authors.lastname: Wang
authors.forename: Xin-Lei
authors.initials: XL
authors.lastname: Guan
authors.forename: Han
authors.initials: H
authors.lastname: Luo
authors.forename: Ming
authors.initials: M
authors.lastname: Ni
authors.forename: Jing-Wen
authors.initials: JW
authors.lastname: Yang
authors.forename: Ming-Xing
authors.initials: MX
authors.lastname: Li
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Chen
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051150:Methionine Sulfoxide Reductases / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C100745:Aif1 protein, rat; D000975:Antioxidants; D015415:Biomarkers; D002135:Calcium-Binding Proteins; D016207:Cytokines; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D051150:Methionine Sulfoxide Reductases; D020794:Receptor Protein-Tyrosine Kinases; C483815:Ros1 protein, rat; D020929:Mitogen-Activated Protein Kinase Kinases