title: Poly (I:C) therapy decreases cerebral ischaemia/reperfusion injury via TLR3-mediated prevention of Fas/FADD interaction.
abstract: Toll-like receptor (TLR)-mediated signalling plays a role in cerebral ischaemia/reperfusion (I/R) injury. Modulation of TLRs has been reported to protect against cerebral I/R injury. This study examined whether modulation of TLR3 with poly (I:C) will induce protection against cerebral I/R injury. Mice were treated with or without Poly (I:C) (n = 8/group) 1 hr prior to cerebral ischaemia (60 min.) followed by reperfusion (24 hrs). Poly (I:C) pre-treatment significantly reduced the infarct volume by 57.2% compared with untreated I/R mice. Therapeutic administration of Poly (I:C), administered 30 min. after cerebral ischaemia, markedly decreased infarct volume by 34.9%. However, Poly (I:C)-induced protection was lost in TLR3 knockout mice. In poly (I:C)-treated mice, there was less neuronal damage in the hippocampus compared with untreated I/R mice. Poly (I:C) treatment induced IRF3 phosphorylation, but it inhibited NF-κB activation in the brain. Poly (I:C) also decreased I/R-induced apoptosis by attenuation of Fas/FasL-mediated apoptotic signalling. In addition, Poly (I:C) treatment decreased microglial cell caspase-3 activity. In vitro data showed that Poly (I:C) prevented hypoxia/reoxygenation (H/R)-induced interaction between Fas and FADD as well as caspase-3 and -8 activation in microglial cells. Importantly, Poly (I:C) treatment induced co-association between TLR3 and Fas. Our data suggest that Poly (I:C) decreases in cerebral I/R injury via TLR3 which associates with Fas, thereby preventing the interaction of Fas and FADD, as well as microglial cell caspase-3 and -8 activities. We conclude that TLR3 modulation by Poly (I:C) could be a potential approach for protection against ischaemic stroke.
authors.affiliation: Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.forename: Tuanzhu
authors.initials: T
authors.lastname: Ha
authors.forename: Chen
authors.initials: C
authors.lastname: Lu
authors.forename: Fred
authors.initials: F
authors.lastname: Lam
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: John
authors.initials: J
authors.lastname: Schweitzer
authors.forename: John
authors.initials: J
authors.lastname: Kalbfleisch
authors.forename: Race L
authors.initials: RL
authors.lastname: Kao
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.forename: Chuanfu
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000503:physiopathology; D053148:Caspase 3 / Q000096:biosynthesis / Q000378:metabolism; D053181:Caspase 8 / Q000096:biosynthesis / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D002544:Cerebral Infarction / Q000188:drug therapy*; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use; D011070:Poly I-C / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000188:drug therapy; D051196:Toll-Like Receptor 3 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: C505534:Fadd protein, mouse; C491899:Fas protein, mouse; D053200:Fas-Associated Death Domain Protein; D016328:NF-kappa B; D018696:Neuroprotective Agents; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D019014:fas Receptor; D053148:Caspase 3; D053181:Caspase 8; D011070:Poly I-C
keywords: Poly (I:C); TLR3; apoptosis; cerebral ischaemia/reperfusion; microglial cells; stroke