Toll-like receptor 4-mediated microglial inflammation exacerbates early white matter injury following experimental subarachnoid hemorrhage

作者全名："Peng, Jianhua; Xie, Yuke; Pang, Jinwei; Wu, Yue; Zhou, Jian; Gu, Long; Guo, Kecheng; Zhang, Lifang; Xie, Bingqing; Yin, Shigang; Sun, Xiaochuan; Chen, Ligang; Jiang, Yong"

作者地址："[Peng, Jianhua; Pang, Jinwei; Zhou, Jian; Chen, Ligang; Jiang, Yong] Southwest Med Univ, Affiliated Hosp, Dept Neurosurg, Luzhou, Peoples R China; [Peng, Jianhua; Xie, Yuke; Pang, Jinwei; Zhou, Jian; Gu, Long; Guo, Kecheng; Zhang, Lifang; Xie, Bingqing; Yin, Shigang; Chen, Ligang; Jiang, Yong] Southwest Med Univ, Affiliated Hosp, Lab Neurol Dis & Brain Funct, Luzhou, Peoples R China; [Peng, Jianhua; Pang, Jinwei; Xie, Bingqing; Jiang, Yong] Southwest Med Univ, Inst Epigenet & Brain Sci, Luzhou, Peoples R China; [Peng, Jianhua; Yin, Shigang; Jiang, Yong] Southwest Med Univ, Affiliated Hosp, Academician Expert Workstat Sichuan Prov, Luzhou, Peoples R China; [Wu, Yue] Chongqing Med Univ, Affiliated Hosp 1, Dept Neurosurg, Chongqing, Peoples R China; [Zhang, Lifang; Chen, Ligang] Southwest Med Univ, Affiliated Hosp, Sichuan Clin Res Ctr Neurosurg, Luzhou, Peoples R China; [Jiang, Yong] Southwest Med Univ, Affiliated Hosp, Dept Neurosurg, 25 Taiping St, Luzhou 646000, Peoples R China"

通信作者："Jiang, Y (通讯作者)，Southwest Med Univ, Affiliated Hosp, Dept Neurosurg, 25 Taiping St, Luzhou 646000, Peoples R China."

来源：JOURNAL OF NEUROCHEMISTRY

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001007545800001

JCR分区：Q2

影响因子：4.2

年份：2023

卷号：166

期号：2

开始页：280

结束页：293

文献类型：Article

关键词：microglia; neuroinflammation; subarachnoid hemorrhage; white matter injury

摘要："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 T-2 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-?B, 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."

基金机构："Luzhou Government-Southwest Medical University Strategic Cooperation Project [2021LZXNYD-P01]; National Natural Science Foundation of China [81971132, 82271306]; Sichuan Science and Technology Program [2021ZYD0091, 2021ZYD0106, 2022NSFSC1421, 2022YFS0615, 2023NSFSC0028, 2023NSFSC1559, 2023YFH0069]; Southwest Medical University Project [2021ZKZD013]; Young Elite Scientist Sponsorship Program by the China Association for Science and Technology [YESS20200178]"

基金资助正文："Luzhou Government-Southwest Medical University Strategic Cooperation Project, Grant/Award Number: 2021LZXNYD-P01; National Natural Science Foundation of China, Grant/Award Number: 81971132 and 82271306; Sichuan Science and Technology Program, Grant/Award Number: 2021ZYD0091, 2021ZYD0106, 2022NSFSC1421, 2022YFS0615, 2023NSFSC0028, 2023NSFSC1559 and 2023YFH0069; Southwest Medical University Project, Grant/Award Number: 2021ZKZD013; Young Elite Scientist Sponsorship Program by the China Association for Science and Technology, Grant/Award Number: YESS20200178"