LPS preconditioning redirects TLR signaling following stroke: TRIF-IRF3 plays a seminal role in mediating tolerance to ischemic injury.
LPS preconditioning redirects TLR signaling following stroke: TRIF-IRF3 plays a seminal role in mediating tolerance to ischemic injury.
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DOI：
10.1186/1742-2094-8-140
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发表时间：
2011-10-14
影响因子：
9.3
通讯作者：
Stenzel-Poore MP
中科院分区：
文献类型：
--
作者：
Vartanian KB;Stevens SL;Marsh BJ;Williams-Karnesky R;Lessov NS;Stenzel-Poore MP
Toll样受体4（TLR 4）响应于脑缺血而被激活，导致实质性脑损伤。相反，通过在脑缺血前低剂量暴露于脂多糖（LPS）的预处理轻度激活TLR 4通过重新编程对损伤的信号应答而显著改善结果。这表明TLR 4信号传导可以被改变以诱导内源性神经保护表型。然而，这种神经保护反应中涉及的TLR 4信号传导事件知之甚少。在这里，我们定义了几个分子介导的主要信号级联诱导的LPS预处理，引起重编程反应脑缺血，并赋予神经保护表型。C57 BL 6小鼠在短暂性大脑中动脉闭塞（MCAO）之前用低剂量LPS预处理。在MCAO后收集皮质组织和血液。进行微阵列和qtPCR以分析与TLR 4信号传导相关的基因表达。EMSA和DNA结合ELISA法检测NFκB和IRF 3活性。使用Western印迹或ELISA测定蛋白质表达。MyD 88-/-和TRIF-/-小鼠用于评估LPS预处理诱导的神经保护中的信号传导。基因表达分析表明，LPS预处理导致抗炎/I型IFN相关基因缺血后的显着上调，而促炎基因诱导缺血后存在，但不差异调节LPS。有趣的是，虽然观察到促炎基因的表达，但在中风后LPS预处理的小鼠中，NFκB p65的活性降低，NFκB抑制剂（包括Ship 1、Tollip和p105）的存在增加。相反，IRF 3活性在中风后LPS预处理的小鼠中增强。TRIF和MyD 88缺陷小鼠揭示了LPS诱导的神经保护作用依赖于TLR 4通过TRIF的信号传导，TRIF激活IRF 3，但不依赖于MyD 88信号传导。我们的研究结果表征了与神经保护相关的TLR 4信号传导事件的几个关键介质。LPS预处理通过抑制NFκB活性、增强IRF 3活性和增加抗炎/I型IFN基因表达来重定向TLR 4信号转导以响应卒中。有趣的是，这种保护性表型不需要抑制促炎介质。此外，我们的研究结果强调了TRIF-IRF 3信号作为中风神经保护反应的控制机制的关键作用。
Toll-like receptor 4 (TLR4) is activated in response to cerebral ischemia leading to substantial brain damage. In contrast, mild activation of TLR4 by preconditioning with low dose exposure to lipopolysaccharide (LPS) prior to cerebral ischemia dramatically improves outcome by reprogramming the signaling response to injury. This suggests that TLR4 signaling can be altered to induce an endogenously neuroprotective phenotype. However, the TLR4 signaling events involved in this neuroprotective response are poorly understood. Here we define several molecular mediators of the primary signaling cascades induced by LPS preconditioning that give rise to the reprogrammed response to cerebral ischemia and confer the neuroprotective phenotype. C57BL6 mice were preconditioned with low dose LPS prior to transient middle cerebral artery occlusion (MCAO). Cortical tissue and blood were collected following MCAO. Microarray and qtPCR were performed to analyze gene expression associated with TLR4 signaling. EMSA and DNA binding ELISA were used to evaluate NFκB and IRF3 activity. Protein expression was determined using Western blot or ELISA. MyD88-/- and TRIF-/- mice were utilized to evaluate signaling in LPS preconditioning-induced neuroprotection. Gene expression analyses revealed that LPS preconditioning resulted in a marked upregulation of anti-inflammatory/type I IFN-associated genes following ischemia while pro-inflammatory genes induced following ischemia were present but not differentially modulated by LPS. Interestingly, although expression of pro-inflammatory genes was observed, there was decreased activity of NFκB p65 and increased presence of NFκB inhibitors, including Ship1, Tollip, and p105, in LPS-preconditioned mice following stroke. In contrast, IRF3 activity was enhanced in LPS-preconditioned mice following stroke. TRIF and MyD88 deficient mice revealed that neuroprotection induced by LPS depends on TLR4 signaling via TRIF, which activates IRF3, but does not depend on MyD88 signaling. Our results characterize several critical mediators of the TLR4 signaling events associated with neuroprotection. LPS preconditioning redirects TLR4 signaling in response to stroke through suppression of NFκB activity, enhanced IRF3 activity, and increased anti-inflammatory/type I IFN gene expression. Interestingly, this protective phenotype does not require the suppression of pro-inflammatory mediators. Furthermore, our results highlight a critical role for TRIF-IRF3 signaling as the governing mechanism in the neuroprotective response to stroke.
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DOI：
10.1073/pnas.96.14.8212
发表时间：
1999-07-06
影响因子：
11.1
作者：
Kaul, M;Lipton, SA
通讯作者：
Lipton, SA
DOI：
10.1097/00004647-199802000-00008
发表时间：
1998-02-01
影响因子：
6.3
作者：
Loddick, SA;Turnbull, AV;Rothwell, NJ
通讯作者：
Rothwell, NJ
影响因子：
37.8
作者：
Caso, Javier R.;Pradillo, Jesus M.;Lizasoain, Ignacio
通讯作者：
Lizasoain, Ignacio
影响因子：
8.3
作者：
Barber, PA;Darby, DG;Davis, SM
通讯作者：
Davis, SM
影响因子：
8.3
作者：
Gelderblom, Mathias;Leypoldt, Frank;Magnus, Tim
通讯作者：
Magnus, Tim