Toll‐like receptor 4‐mediated microglial inflammation exacerbates early white matter injury following experimental subarachnoid hemorrhage
Toll‐like receptor 4‐mediated microglial inflammation exacerbates early white matter injury following experimental subarachnoid hemorrhage
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DOI：
10.1111/jnc.15851
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发表时间：
2023-06
影响因子：
4.7
通讯作者：
Jianhua Peng;Yuke Xie;Jinwei Pang;Yue Wu;Jian Zhou;Long Gu;Kecheng Guo;Lifang Zhang;Bingqing Xie;Shigang Yin;Xiaochuan Sun;Ligang Chen;Yong Jiang
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文献类型：
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作者：
Jianhua Peng;Yuke Xie;Jinwei Pang;Yue Wu;Jian Zhou;Long Gu;Kecheng Guo;Lifang Zhang;Bingqing Xie;Shigang Yin;Xiaochuan Sun;Ligang Chen;Yong Jiang
据报道，神经炎症与蛛网膜下腔出血（SAH）后的白质损伤（WMI）有关。作为大脑的主要常驻免疫细胞，小胶质细胞可以被激活为促炎和抗炎表型。 Toll 样受体 4 (TLR4) 表达于小胶质细胞表面，在小胶质细胞炎症中发挥关键作用。然而，SAH 后 TLR4、小胶质细胞极化和 WMI 之间的关系仍不清楚。在这项研究中，总共使用了 121 只雄性成年 C57BL/6 野生型 (WT) 小鼠、20 只出生后第 1 天 (P1) 的 WT 小鼠和 41 只雄性成年 TLR4 基因敲除 (TLR4−/−) 小鼠，通过放射学、组织学、微观结构、转录和细胞学证据来研究 TLR4 诱导的小胶质细胞极化在 SAH 后早期 WMI 中的潜在作用。结果表明，小胶质细胞炎症与髓磷脂损失和轴突损伤有关，表现为髓磷脂碱性蛋白（MBP）减少，以及降解髓磷脂碱性蛋白（dMBP）和淀粉样前体蛋白（APP）增加。 TLR4 基因敲除使小胶质细胞极化向抗炎表型转变，并在 SAH 后早期（24 小时）保护白质，如有毒代谢物减少、髓磷脂保存、APP 积累减少、白质 T2 高信号减少和 FA 值增加所示。建立小胶质细胞和少突胶质细胞（负责髓鞘生成和维持的细胞）的共培养，以进一步阐明小胶质细胞极化与 WMI 之间的关系。在体外，TLR4 抑制降低了小胶质细胞 MyD88 和磷酸化 NF-κB 的表达，从而抑制 M1 极化并减轻炎症。小胶质细胞中 TLR4 的减少增加了邻近少突胶质细胞的保存。总之，小胶质细胞炎症对实验性 SAH 后的早期 WMI 有双重影响。未来有必要探索更多临床相关的调节神经炎症的方法，以通过 WMI 和灰质破坏来对抗中风。
Neuroinflammation has been reported to be associated with white matter injury (WMI) after subarachnoid hemorrhage (SAH). As the main resident immune cells of the brain, microglia can be activated into proinflammatory and anti‐inflammatory phenotypes. Toll‐like receptor 4 (TLR4), expressed on the surface of the microglia, plays a key role in microglial inflammation. However, the relationship between TLR4, microglial polarization, and WMI following SAH remains unclear. In this study, a total of 121 male adult C57BL/6 wild‐type (WT) mice, 20 WT mice at postnatal day 1 (P1), and 41 male adult TLR4 gene knockout (TLR4−/−) mice were used to investigate the potential role of TLR4‐induced microglial polarization in early WMI after SAH by radiological, histological, microstructural, transcriptional, and cytological evidence. The results indicated that microglial inflammation was associated with myelin loss and axon damage, shown as a decrease in myelin basic protein (MBP), as well as increase in degraded myelin basic protein (dMBP) and amyloid precursor protein (APP). Gene knockout of TLR4 revised microglial polarization toward the anti‐inflammatory phenotype and protected the white matter at an early phase after SAH (24 h), as shown through reduction of toxic metabolites, preservation of myelin, reductions in APP accumulation, reductions in white matter T2 hyperintensity, and increases in FA values. Cocultures of microglia and oligodendrocytes, the cells responsible for myelin production and maintenance, were established to further elucidate the relationship between microglial polarization and WMI. In vitro, TLR4 inhibition decreased the expression of microglial MyD88 and phosphorylated NF‐κB, thereby inhibiting M1 polarization and mitigating inflammation. Decrease in TLR4 in the microglia increased preservation of neighboring oligodendrocytes. In conclusion, microglial inflammation has dual effects on early WMI after experimental SAH. Future explorations on more clinically relevant methods for modulating neuroinflammation are warranted to combat stroke with both WMI and gray matter destruction.