Heme activates TLR4-mediated inflammatory injury via MyD88/TRIF signaling pathway in intracerebral hemorrhage.
Heme activates TLR4-mediated inflammatory injury via MyD88/TRIF signaling pathway in intracerebral hemorrhage.
复制标题
血红素在脑出血中通过 MyD88/TRIF 信号通路激活 TLR4 介导的炎症损伤。
DOI：
10.1186/1742-2094-9-46
复制
发表时间：
2012-03-06
影响因子：
9.3
通讯作者：
Yang QW
中科院分区：
文献类型：
--
作者：
Lin S;Yin Q;Zhong Q;Lv FL;Zhou Y;Li JQ;Wang JZ;Su BY;Yang QW
炎症损伤在脑出血（ICH）诱导的神经功能缺损中起着关键作用;然而，上游细胞事件触发先天免疫和炎症反应导致神经功能缺损的信号传导途径并不明显。Toll样受体4（TLR 4）在脑疾病引起的炎性损伤中起作用。在这项研究中，我们研究了TLR 4信号在ICH诱导的炎症中的作用。在ICH模型中，使用实时RT-PCR已经证明了反应性小胶质细胞中TLR 4表达的显著上调。采用免疫组化法检测小胶质细胞的活化，ELISA法检测细胞因子的表达，Western blot和EMSA法检测MyD 88、TRIF和NF-κB的表达，动物行为学评价动物行为。与WT小鼠相比，TLR 4 −/−小鼠抑制了ICH诱导的脑损伤，表现为脑水肿减轻和神经功能缺损评分降低。对TLR 4 −/−、MyD 88 −/−和TRIF−/−小鼠血肿周围组织中的细胞因子（包括IL-6、TNF-α和IL-1β）进行定量以及对巨噬细胞浸润进行评估，结果显示ICH后炎症损伤减弱。TLR 4 −/−小鼠也表现出MyD 88和TRIF表达降低，伴随着NF-κB活性降低。提示脑出血后MyD 88和TRIF通路均可能通过NF-κB活化参与TLR 4介导的炎症损伤。外源性氯化血红素给药显著增加了培养物中TLR 4的表达和小胶质细胞的活化，也加重了WT小鼠的脑损伤，但在TLR 4 −/−小鼠中没有。抗TLR 4抗体给药抑制了培养物和ICH小鼠模型中氯化血红素诱导的小胶质细胞活化。我们的研究结果表明，血红素通过TLR 4增强小胶质细胞活化，进而通过MyD 88/TRIF信号通路诱导NF-κB活化，并最终增加ICH中细胞因子表达和炎性损伤。靶向TLR 4信号转导可能是ICH的一种有前途的治疗策略。
Inflammatory injury plays a critical role in intracerebral hemorrhage (ICH)-induced neurological deficits; however, the signaling pathways are not apparent by which the upstream cellular events trigger innate immune and inflammatory responses that contribute to neurological impairments. Toll-like receptor 4 (TLR4) plays a role in inflammatory damage caused by brain disorders. In this study, we investigate the role of TLR4 signaling in ICH-induced inflammation. In the ICH model, a significant upregulation of TLR4 expression in reactive microglia has been demonstrated using real-time RT-PCR. Activation of microglia was detected by immunohistochemistry, cytokines were measured by ELISA, MyD88, TRIF and NF-κB were measured by Western blot and EMSA, animal behavior was evaluated by animal behavioristics. Compared to WT mice, TLR4−/− mice had restrained ICH-induced brain damage showing in reduced cerebral edema and lower neurological deficit scores. Quantification of cytokines including IL-6, TNF-α and IL-1β and assessment of macrophage infiltration in perihematoma tissues from TLR4−/−, MyD88−/− and TRIF−/− mice showed attenuated inflammatory damage after ICH. TLR4−/− mice also exhibited reduced MyD88 and TRIF expression which was accompanied by decreased NF-κB activity. This suggests that after ICH both MyD88 and TRIF pathways might be involved in TLR4-mediated inflammatory injury possibly via NF-κB activation. Exogenous hemin administration significantly increased TLR4 expression and microglial activation in cultures and also exacerbated brain injury in WT mice but not in TLR4−/− mice. Anti-TLR4 antibody administration suppressed hemin-induced microglial activation in cultures and in the mice model of ICH. Our findings suggest that heme potentiates microglial activation via TLR4, in turn inducing NF-κB activation via the MyD88/TRIF signaling pathway, and ultimately increasing cytokine expression and inflammatory injury in ICH. Targeting TLR4 signaling may be a promising therapeutic strategy for ICH.
登录
查看更多内容
脑癌敲除小鼠中脑出血后纹状体损伤和行为缺陷增加。
影响因子：
4.1
作者：
Chen L;Zhang X;Chen-Roetling J;Regan RF
通讯作者：
Regan RF
DOI：
10.1016/s0169-328x(02)00417-5
发表时间：
2002-10-15
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Bond, BC;Virley, DJ;Preece, P
通讯作者：
Preece, P
影响因子：
8.3
作者：
Park, S;Yamaguchi, M;Zhang, JH
通讯作者：
Zhang, JH
影响因子：
6
作者：
Chang, Che-Feng;Chen, Shu-Fen;Shyue, Song-Kun
通讯作者：
Shyue, Song-Kun
影响因子：
9.9
作者：
Castillo, J;Dávalos, A;Kase, CS
通讯作者：
Kase, CS