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: Xia Zhang, Tuanzhu Ha, Chen Lu, Fred Lam, Li Liu, John Schweitzer, John Kalbfleisch, Race L Kao, David L Williams, Chuanfu Li
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 19 Issue 3 Pg. 555-65 (Mar 2015) ISSN: 1582-4934 [Electronic] England
• PMID: 25351293 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• Fadd protein, mouse
• Fas protein, mouse
• Fas-Associated Death Domain Protein
• NF-kappa B
• Neuroprotective Agents
• TLR3 protein, mouse
• Toll-Like Receptor 3
• fas Receptor
• Caspase 3
• Caspase 8
• Poly I-C

Topics

• Animals
• Apoptosis (drug effects)
• Brain (blood supply, physiopathology)
• Caspase 3 (biosynthesis, metabolism)
• Caspase 8 (biosynthesis, metabolism)
• Cell Hypoxia (drug effects)
• Cerebral Infarction (drug therapy)
• Fas-Associated Death Domain Protein (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (metabolism)
• Neuroprotective Agents (therapeutic use)
• Poly I-C (therapeutic use)
• Reperfusion Injury (drug therapy)
• Toll-Like Receptor 3 (biosynthesis, genetics, metabolism)
• fas Receptor (metabolism)