Differential role of TLR2 and TLR4 in acute brain injury induced by cerebral ischenua/reperfusion

【Author】

KAO Race L;KELLEY Jim L;WILLIAMS David L;

【Abstract】

<正>A growing body of evidence suggests that immune and inflammatory responses contribute to cerebral ischemia/reperfusion(I/R)induced injury.Toll-like receptors(TLRs)have been demonstrated to play a critical role in the induction of innate and inflammatory responses.Recently,TLR2 and TLR4 have been implicated in cerebral I/R injury,however,the molecular mechanisms that underlie the involvement of TLR2 and TLR4 in cerebral I/R injury are unknown.In present study,we evaluated brain infarct size,neurological function,mortality,differential regulation of PI3K/Akt signaling and NF-kappa-B activation pathway in TLR2 knockout mice(TLR2~(-/-))and TLR4 knockout(TLR4~(-/-))mice subjected to left middle cerebral artery occlusion(MCAO)for 60 min followed by reperfusion for 24 h.Age-matched wild type(WT)mice subjected to cerebral I/R were used as control.The results showed that,compared with TLR4~(-/-)mice,in TLR2~(-/-)mice,infarct size(19.3±1.6 vs 9.4±2.2)and mortality(44.8%vs 24.2%) were increased,neurological function(2.2±0.5 vs 3.9±0.6)was decreased,the levels of phospho-Akt(0.21±0.03) and phospho-P70S6K(0.52±0.04)were decreased,phosphorylation of inhibitor of kappa-Bα(p-IκBα,2.42±0.37) and NF-kappa-B[(2.6±0.1)×l0~5]activity were increased.In contrast,compared with WT and TLR2~(-/-)mice,in TLR4~(-/-)mice,the infarct size(2.6±1.2 vs 9.4±2.2)and improved neurological function(6.7±0.8 vs 3.9±0.6)were observed 24 h after cerebral I/R.In addition,the levels of phospho-Akt(0.88±0.16)and phospho-P70S6K(0.79±0.04) were increased,and p-IκBα(0.86±0.06)and NF-kappa-B[(0.8±0.1)×l0~5]activity were decreased.Our data demonstrate that TLR2 and TLR4 play different roles in the pathophysiological process after cerebral I/R.TLR2 deficiency resulted in decreased activation of the protective PI3K/Akt pathway and did not attenuate NF-kappa-B activation induced by cerebral I/R,which may aggravate brain damage after acute focal cerebral I/R.In contrast, TLR4 deficiency enhanced the activation of PI3K/Akt pathway and inhibited NF-kappa-B activation following cerebral I/R,which may attenuate brain damage after acute focal cerebral I/R.

【Keywords】

TLR2;;TLR4;;cerebral;;ischemia

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