Differential roles of TLR2 and TLR4 in acute focal cerebral ischemia/reperfusion injury in mice

• Type of Material: Article
• Authors: Fang Hua, Emory University; Jing Ma, East Tennessee State University; Tuanzhu Ha, East Tennessee State University; Jim L. Kelley, East Tennessee State University; Race L. Kao, East Tennessee State University; John B. Schweitzer, East Tennessee State University; John H. Kalbfleisch, East Tennessee State University; David L. Williams, East Tennessee State University; Chuanfu Li, East Tennessee State University
• Language: English
• Date: 2009-03-25
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 Elsevier B.V. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.brainres.2009.01.018
• Title of Journal or Parent Work: Brain Research
• ISSN: 0006-8993
• Volume: 1262
• Start Page: 100
• End Page: 108
• Grant/Funding Information: This work was supported by AHA postdoctoral fellowship 0625348B and AHA Scientist Development Grant 0830481N to FH; ETSU RDC Grant to RLK; NIH RO1GM53552 to DLW and NIH RO1HL071837 to CL.
• Keywords: TLR4; mouse; TLR2; ischemia/reperfusion; cerebral
• Research Categories: Biology, Neuroscience; Health Sciences, Pathology; Health Sciences, Medicine and Surgery

Abstract

Recent studies have shown that Toll-like receptors (TLRs) are involved in cerebral ischemia/reperfusion (I/R) injury. This study was to investigate the role of TLR2 and TLR4 in acute focal cerebral I/R injury. Cerebral infarct size, neurological function and mortality were evaluated. NFκB binding activity, phosphorylation of IκBα, Akt and ERK1/2 were examined in ischemic cerebral tissue by EMSA and Western blots. Compared to wild type (WT) mice, in TLR4 knockout (TLR4KO) mice, brain infarct size was decreased (2.6 ± 1.18% vs 11.6 ± 1.97% of whole cerebral volume, p<0.05) and neurological function was maintained (7.3 ± 0.79 vs 4.7 ± 0.68, p<0.05). However, compared to TLR4KO mice, TLR2 knockout (TLR2KO) mice showed higher mortality (38.2% vs 13.0%, p<0.05), decreased neurological function (2.9 ± 0.53 vs 7.3 ± 0.79, p<0.05) and increased brain infarct size (19.1 ± 1.33% vs 2.6 ± 1.18%, p<0.05). NFκB activation and IκBα phosphorylation were attenuated in TLR4KO mice (1.09 ± 0.02 and 1.2 ± 0.04) compared to TLR2KO mice (1.31 ± 0.02 and 2.2 ± 0.32) after cerebral ischemia. Compared to TLR4KO mice, in TLR2KO mice, the phosphorylation of Akt (0.2 ± 0.03 vs 0.9 ± 0.16, p<0.05) and ERK1/2 (0.8 ± 0.06 vs 1.3 ± 0.17) evoked by cerebral I/R was attenuated. The present study demonstrates that TLR2 and TLR4 play differential roles in acute cerebral I/R injury. Specifically, TLR4 contributes to cerebral I/R injury, while TLR2 appears to be neuroprotective by enhancing the activation of protective signaling in response to cerebral I/R.