Poly (I:C) therapy decreases cerebral ischaemia/reperfusion injury via TLR 3‐mediated prevention of Fas/ FADD interaction

Toll‐like receptor ( TLR )‐mediated signalling plays a role in cerebral ischaemia/reperfusion (I/R) injury. Modulation of TLR s has been reported to protect against cerebral I/R injury. This study examined whether modulation of TLR 3 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 TLR 3 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 IRF 3 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 TLR 3 and Fas. Our data suggest that Poly (I:C) decreases in cerebral I/R injury via TLR 3 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 TLR 3 modulation by Poly (I:C) could be a potential approach for protection against ischaemic stroke.