title: Liver X receptor-dependent inhibition of microglial nitric oxide synthase 2.
abstract: BACKGROUND
  The nuclear receptor liver X receptor (LXR) exerts transcriptional control over lipid metabolism and inflammatory response in cells of the myeloid lineage, suggesting that LXR may be a potential target in a number of chronic neuroinflammatory and neurodegenerative diseases where persistent microglial activation has been implicated in the pathogenesis.
  
  
  METHODS
  The effect of LXR activation on microglia and central nervous system (CNS) inflammation was studied using a synthetic LXR agonist in cultured microglia, a microglial cell line and experimental allergic encephalomyelitis (EAE), an animal model of CNS inflammation.
  
  
  RESULTS
  LXR activation inhibited nitric oxide synthase 2, inducible (Nos2) expression and nitric oxide production in lipopolysaccharide (LPS)-stimulated microglia. Inhibition of microglial activation in response to interferon-γ was less reliable. In LPS-stimulated cells, LXR activation did not inhibit nuclear translocation of NF-kappaB1 p50. Instead, LXR-dependent Nos2 repression was associated with inhibition of histone 4 acetylation and inhibition of NF-kappaB1 p50 binding at the Nos2 promoter. Histone acetylation and NF-kappaB1 p50 binding were mechanistically linked, and histone deacetylase (HDAC) activity appeared to be important for LXR-dependent transcriptional repression of Nos2. Analysis of CNS gene expression in animals undergoing EAE showed that the expressions of Lxr and LXR-dependent genes were downregulated during CNS inflammation. Nevertheless, administration of LXR agonist GW3965 during the effector phase of EAE delayed the onset of clinical disease and reversed the diminished expression of LXR-dependent reverse cholesterol transport genes. However, the CNS expressions of Nos2 and other inflammatory genes were not significantly inhibited by LXR activation in EAE, and clinical disease severity was comparable to vehicle controls at later time points in LXR agonist treated animals.
  
  
  CONCLUSIONS
  LXR can be targeted to modulate microglial activation. LXR-dependent repression of inflammatory genes may be stimulus-dependent and impaired by HDAC inhibition. Endogenous LXR activity does not appear to modulate CNS inflammation, but LXR activity can be partially restored in the CNS by administration of exogenous LXR agonist with an impact on clinical disease severity at early, but not late, time points in EAE.
authors.affiliation: Department of Neurology, Virginia Commonwealth University School of Medicine, PO Box 980599, VA, 23298, Richmond, USA. jrmcvoy@vcu.edu.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Secor McVoy
authors.affiliation: Department of Neurology, Virginia Commonwealth University School of Medicine, PO Box 980599, VA, 23298, Richmond, USA. hanadi.ajam@gmail.com.
authors.forename: Hanadi Ajam
authors.initials: HA
authors.lastname: Oughli
authors.affiliation: Department of Neurology, Virginia Commonwealth University School of Medicine, PO Box 980599, VA, 23298, Richmond, USA. uoh@vcu.edu.
authors.forename: Unsong
authors.initials: U
authors.lastname: Oh
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001565:Benzoates / Q000627:therapeutic use; D001596:Benzylamines / Q000627:therapeutic use; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000378:metabolism*; D003851:Deoxyribonucleases / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000473:pathology / Q000628:therapy; D020869:Gene Expression Profiling; D006657:Histones / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology / Q000633:toxicity; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010446:Peptide Fragments / Q000276:immunology / Q000633:toxicity; D011485:Protein Binding / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
chemical_list: D001565:Benzoates; D001596:Benzylamines; D016207:Cytokines; C473027:GW 3965; D006657:Histones; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; D063308:Myelin-Oligodendrocyte Glycoprotein; D057093:Orphan Nuclear Receptors; D010446:Peptide Fragments; D034741:RNA, Small Interfering; C445081:myelin oligodendrocyte glycoprotein (35-55); D052247:Nitric Oxide Synthase Type II; D003851:Deoxyribonucleases