Microglial TLR4 is Critical for Neuronal Injury and Cognitive Dysfunction in Subarachnoid Hemorrhage.
Microglial TLR4 is Critical for Neuronal Injury and Cognitive Dysfunction in Subarachnoid Hemorrhage.
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DOI：
10.1007/s12028-022-01552-w
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发表时间：
2022-12
影响因子：
3.5
通讯作者：
中科院分区：
文献类型：
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作者：
Toll样受体4（TLR 4）激活导致促炎介质的过度产生和共刺激分子的表达增加，导致蛛网膜下腔出血（SAH）后的神经炎症。虽然TLR 4介导的炎症通路在神经炎症中已经研究了很长时间，但在SAH中神经炎症的起始和传播中涉及的特定胶质细胞尚未得到很好的阐明。在这项研究中，我们研究了胶质细胞TLR 4，包括小胶质细胞和星形胶质细胞在脑损伤和神经功能不良的结果参与。在本研究中，使用了整体TLR 4敲除、细胞特异性TLR 4敲除和双杂交对照雄性和雌性小鼠。在小鼠中脑附近注射60 μl自体血以诱导SAH;在术后第7天对动物实施安乐死，以进行神经胶质细胞和凋亡细胞的免疫组织化学。通过使用免疫荧光密度定量来评估小胶质细胞形态，以确定形态和神经炎症之间的相关性。小胶质细胞耗竭是通过脑室内注射氯膦酸盐脂质体完成的。采用巴恩斯迷宫评定认知功能。在SAH诱导后的术后第7天，与磷酸盐缓冲盐水对照脂质体相比，氯膦酸盐脂质体组的神经元凋亡显著减少，并且氯膦酸盐组的认知能力也得到改善。与细胞特异性和整体TLR 4基因敲除相比，野生型基因敲除中小胶质细胞活化（通过形态测定分析评估）和神经元凋亡的差异显著更大。星形胶质细胞和神经元上缺乏TLR 4的小鼠与野生型小鼠相比在任何终点上都没有差异。我们的数据表明，小胶质细胞耗竭与脑室内注射氯膦酸盐可以改善SAH小鼠模型的认知功能，TLR 4是小胶质细胞活化和神经元损伤的关键。只有小胶质细胞TLR 4是脑损伤和不良认知结果所必需的，而不是星形胶质细胞或神经元TLR 4。因此，小胶质细胞TLR 4可能是治疗SAH相关神经元损伤和防止认知功能障碍的有效治疗靶点。
Toll-like receptor 4 (TLR4) activation causes excessive production of proinflammatory mediators and an increased expression of costimulatory molecules that leads to neuroinflammation after subarachnoid hemorrhage (SAH). Although TLR4-mediated inflammatory pathways have long been studied in neuroinflammation, the specific glia implicated in initiation and propagation of neuroinflammation in SAH have not been well elucidated. In this study, we investigated the involvement of glial TLR4 including microglia and astrocytes in brain damage and poor neurological outcome. In this study, global TLR4 knockout, cell-specific TLR4 knockout, and floxxed control male and female mice were used. The mice were injected with 60 μl autologous blood near the mesencephalon to induce SAH; animals were euthanized on postoperative day 7 for immunohistochemistry of glia and apoptotic cells. Microglial morphology was evaluated by using immunofluorescence density quantification to determine correlations between morphology and neuroinflammation. Microglial depletion was accomplished with the intracerebroventricular administration of clodronate liposomes. Cognitive function was assessed with Barnes maze. On postoperative day 7 after SAH induction, neuronal apoptosis was markedly reduced in the clodronate liposome group compared with phosphate-buffered saline control liposomes, and cognitive performance in the clodronate group was improved, as well. Differences in microglial activation, assessed by morphometric analysis, and neuronal apoptosis were significantly greater in wildtype knockouts compared with cell-specific and global TLR4 knockouts. The mice lacking TLR4 on astrocytes and neurons showed no differences compared with wildtype mice on any end points. Our data suggest that microglial depletion with the intracerebroventricular administration of clodronate can improve the cognitive function in an SAH mouse model, and TLR4 is critical for microglial activation and neuronal injury. Only microglial TLR4 is necessary for brain damage and poor cognitive outcome rather than astrocyte or neuronal TLR4. Thus, microglial TLR4 could be a potent therapeutic target to treat SAH-associated neuronal injury and protect against cognitive dysfunction.
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影响因子：
2
作者：
Hanafy, Khalid A.;Stuart, R. Morgan;Khandji, Alexander G.;Connolly, E. Sander;Badjatia, Neeraj;Mayer, Stephan A.;Schindler, Christian
通讯作者：
Schindler, Christian
高铁蛋白是一种内源性Toll样受体4配体与亚蛛网膜下腔出血。
影响因子：
5.6
作者：
Kwon MS;Woo SK;Kurland DB;Yoon SH;Palmer AF;Banerjee U;Iqbal S;Ivanova S;Gerzanich V;Simard JM
通讯作者：
Simard JM
DOI：
10.1523/jneurosci.2102-11.2011
发表时间：
2011-09-07
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Faustino JV;Wang X;Johnson CE;Klibanov A;Derugin N;Wendland MF;Vexler ZS
通讯作者：
Vexler ZS
影响因子：
5.7
作者：
Thomas, Ajith J.;Ascanio-Cortez, Luis;Hanafy, Khalid A.
通讯作者：
Hanafy, Khalid A.
影响因子：
9.3
作者：
LeBlanc RH 3rd;Chen R;Selim MH;Hanafy KA
通讯作者：
Hanafy KA