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Poly (I:C) therapy decreases cerebral ischaemia/reperfusion injury via TLR3-mediated prevention of Fas/FADD
Xia Zhang1, Tuanzhu Ha, Chen Lu
1Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
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.
Insights
Poly (I:C) protects against cerebral ischemia/reperfusion injury by modulating Toll-like receptor 3 (TLR3). This treatment reduces infarct volume and neuronal damage, offering a potential therapeutic strategy for stroke.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Cerebral ischemia/reperfusion (I/R) injury involves Toll-like receptor (TLR)-mediated signaling.
- Modulation of TLRs has shown protective effects against cerebral I/R injury.
Purpose of the Study:
- To investigate if poly (I:C) modulation of TLR3 induces protection against cerebral I/R injury.
- To elucidate the mechanisms underlying poly (I:C)-mediated neuroprotection.
Main Methods:
- Mice were pre-treated or therapeutically treated with poly (I:C) before or after inducing cerebral I/R.
- Infarct volume, neuronal damage, and molecular markers of inflammation and apoptosis were assessed.
- Experiments were conducted in wild-type and TLR3 knockout mice.
- In vitro studies using microglial cells exposed to hypoxia/reoxygenation (H/R) were performed.
Main Results:
- Poly (I:C) pre-treatment significantly reduced infarct volume by 57.2%.
- Therapeutic poly (I:C) administration decreased infarct volume by 34.9%.
- Protection was dependent on TLR3, as it was lost in TLR3 knockout mice.
- Poly (I:C) reduced neuronal damage, inhibited NF-κB activation, decreased apoptosis via the Fas/FasL pathway, and reduced caspase-3 activity in microglia.
- Poly (I:C) induced co-association between TLR3 and Fas, preventing Fas-FADD and caspase-3/-8 activation in microglial cells.
Conclusions:
- Poly (I:C) confers protection against cerebral I/R injury through TLR3.
- The mechanism involves TLR3-Fas association, inhibiting microglial apoptosis and inflammatory signaling.
- TLR3 modulation by poly (I:C) represents a potential therapeutic strategy for ischemic stroke.
