Toll-like Receptor 2/4 Heterodimer Mediates Inflammatory Injury in Intracerebral Hemorrhage
Toll-like Receptor 2/4 Heterodimer Mediates Inflammatory Injury in Intracerebral Hemorrhage
复制标题
Toll 样受体 2/4 异二聚体介导脑出血中的炎症损伤
DOI：
10.1002/ana.24159
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发表时间：
2014-06-01
影响因子：
11.2
通讯作者：
Yang, Qing-Wu
中科院分区：
文献类型：
--
作者：
Wang, Yan-Chun;Zhou, Yu;Yang, Qing-Wu
目的：炎症损伤在脑出血继发性脑损伤中起重要作用。然而，ICH后启动炎症反应的上游事件仍然难以捉摸。我们前期的研究提示Toll样受体4（TLR 4）可能是脑出血炎症损伤的上游信号。此外，最近的临床研究结果表明，TLR 2和TLR 4都可能参与ICH诱导的脑损伤。然而，目前还不清楚TLR 2在ICH诱导的炎性损伤中的作用以及TLR 2与TLR 4的相互作用。方法：在体内和体外ICH模型中研究TLR 2和TLR 2/TLR 4异二聚体在ICH诱导的炎性损伤中的作用。血红蛋白（Hb），而不是其他血液成分，通过组装TLR 2/TLR 4异二聚体触发ICH中的炎性损伤。MyD 88（髓样分化初级反应基因88），而不是TRIF（诱导干扰素β的含有Toll/IR-1结构域的衔接蛋白），是ICH诱导的TLR 2/TLR 4异源二聚化所必需的。MyD 88 Arg 196的突变消除了TLR 2/TLR 4异二聚体。解释：我们的结果表明，一种新的TLR 2/TLR 4异二聚体诱导的血红蛋白在脑出血的炎症损伤。干扰TLR 2/TLR 4异源二聚体的组装可能是开发有效治疗ICH的新靶点。
Objective: Inflammatory injury plays a critical role in intracerebral hemorrhage (ICH)-induced secondary brain injury. However, the upstream events that initiate inflammatory responses following ICH remain elusive. Our previous studies suggested that Toll-like receptor 4 (TLR4) may be the upstream signal that triggers inflammatory injury in ICH. In addition, recent clinical findings indicated that both TLR2 and TLR4 may participate in ICH-induced brain injury. However, it is unclear how TLR2 functions in ICH-induced inflammatory injury and how TLR2 interacts with TLR4.Methods: The role of TLR2 and TLR2/TLR4 heterodimerization in ICH-induced inflammatory injury was investigated in both in vivo and in vitro models of ICH.Results: TLR2 mediated ICH-induced inflammatory injury, which forms a heterodimer with TLR4 in both in vivo and in vitro models of ICH. Hemoglobin (Hb), but not other blood components, triggered inflammatory injury in ICH via assembly of TLR2/TLR4 heterodimers. MyD88 (myeloid differentiation primary response gene 88), but not TRIF (Toll/IR-1 domain-containing adaptor protein inducing interferon-beta), was required for ICH-induced TLR2/TLR4 heterodimerization. Mutation of MyD88 Arg196 abolished the TLR2/TLR4 heterodimerization.Interpretation: Our results suggest that a novel TLR2/TLR4 heterodimer induced by Hb initiates inflammatory injury in ICH. Interfering with the assembly of the TLR2/TLR4 heterodimer may be a novel target for developing effective treatment of ICH.