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

• Published in: Brain research 2009-03, Vol.1262, p.100-108
• Main Authors: Hua, Fang, Ma, Jing, Ha, Tuanzhu, Kelley, Jim L, Kao, Race L, Schweitzer, John B, Kalbfleisch, John H, Williams, David L, Li, Chuanfu
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Biological and medical sciences; Brain - pathology; Brain - physiology; Brain Ischemia - metabolism; Brain Ischemia - pathology; Brain Ischemia - physiopathology; Cerebral; Ischemia/reperfusion; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Mouse; Neurology; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Reperfusion Injury - physiopathology; Stroke - metabolism; Stroke - pathology; Stroke - physiopathology; Survival Rate; TLR2; TLR4; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2009.01.018

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. NFкB binding activity, phosphorylation of IкBα, 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). NFкB activation and IкBα 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.