title: Activation of liver X receptor delayed the retinal degeneration of rd1 mice through modulation of the immunological function of glia.
abstract: Retinal degeneration (RD), including retinitis pigmentosa (RP), is an inherited eye disease characterized by progressive degeneration of photoreceptors. Recently, immune cells, including microglia, Müller cells and astrocytes, in degenerative retina are demonstrated to play key roles in the development of RD and can be used as potential therapeutic targets. Liver X receptors (LXRs) are important immuno-inflammatory response transcription factors that have been reported to be a new potential therapeutic drug target for neurodegenerative diseases. However, the potential therapeutic utility of LXRs for RP has not been evaluated. In the present study, Pde6β (rd1) mice received intraperitoneal injections of T0901317 (T0, 50 mg/kg/d) or vehicle (2% DMSO) for 7 days with age-matched C57/BL6 mice as controls. The effect of T0 was examined by quantitating photoreceptor apoptosis, microglial density and the expression of inflammatory mediators; the underlying mechanisms were then explored with a microarray assay. T0 markedly delayed apoptosis of the photoreceptors, partially through suppressing the activation of microglia and the gliosis of Müller cells, and decreased the expression levels of IL-6, iNOS, COX-2 and ENG in rd1 mice; as a result, the visual function of T0-treated rd1 mice measured with electroretinograms (ERG) was preserved for a longer time than that of vehicle-treated rd1 mice. The microarray assay showed that the Janus kinase/Signal Transducer and Activator of Transcription (JAK-STAT) signaling pathway was significantly affected in the retina of rd1 mice with T0 treatment. Our data suggested that T0 modulated the immunologic function of glia cells in the degenerative retina through the JAK3/STAT pathway and delayed the apoptosis of photoreceptors.
authors.affiliation: Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing, 400038, China.|Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: He
authors.affiliation: Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing, 400038, China.|Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China.
authors.forename: Dayu
authors.initials: D
authors.lastname: Sun
authors.affiliation: Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing, 400038, China.|Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China.
authors.forename: Siyu
authors.initials: S
authors.lastname: Chen
authors.affiliation: Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing, 400038, China.|Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China.
authors.forename: Haiwei
authors.initials: H
authors.lastname: Xu
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005911:Gliosis; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007113:Immunity, Innate / Q000187:drug effects; D053612:Janus Kinases / Q000378:metabolism; D000071518:Liver X Receptors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009457:Neuroglia / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D050791:STAT Transcription Factors / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014785:Vision, Ocular / Q000187:drug effects; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D006845:Hydrocarbons, Fluorinated; D053612:Janus Kinases; D000071518:Liver X Receptors; D050791:STAT Transcription Factors; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
keywords: JAK-STAT pathway; apoptosis; liver X receptors; microglia; retinal degeneration