Poly (I:C) therapy decreases cerebral ischaemia/reperfusion injury via TLR3‐mediated prevention of Fas/FADD interaction

Journal of Cellular and Molecular Medicine

Xia Zhang⁴  Tuanzhu Ha⁴  Chen Lu⁴  Fred Lam⁴  Li Liu²  John Schweitzer³  John Kalbfleisch¹  Race L. Kao⁴  David L. Williams⁴ 

[1] Biometry and Medical Computing and the Center for Inflammation, Quillen College of Medicine, East Tennessee State University, Johnson City, TN;Department of Geriatrics5, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China;Pathology Quillen College of Medicine, East Tennessee State University, Johnson City, TN;Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA

关键词: cerebral ischaemia/reperfusion;    stroke;    TLR3;    Poly (I:C);    apoptosis;    microglial cells;   

DOI  :  10.1111/jcmm.12456

来源: Wiley

【 摘 要 】

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.

【 授权许可】

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© 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

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