TREM2 alleviates white matter injury after traumatic brain injury in mice might be mediated by regulation of DHCR24/LXR pathway in microglia

作者：Li Zhao, Shenghui Yu, Lin Li, Chao Zhou, Lin Wang, Shuang Tang, Nina Gu, Zhaosi Zhang, Zhijian Huang, Hong Chen, Wei Tang, Yingwen Wang, Xiaomin Yang, Xiaochuan Sun, Yan Jin · 发表于：Clinical and Translational Medicine · 年份：2024 · DOI：10.1002/ctm2.1665 · 被引用次数：30 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Neurological Disease Mechanisms and Treatments、Neurogenesis and neuroplasticity mechanisms

BACKGROUND: White matter injury (WMI) is an important pathological process after traumatic brain injury (TBI). The correlation between white matter functions and the myeloid cells expressing triggering receptor-2 (TREM2) has been convincingly demonstrated. Moreover, a recent study revealed that microglial sterol metabolism is crucial for early remyelination after demyelinating diseases. However, the potential roles of TREM2 expression and microglial sterol metabolism in WMI after TBI have not yet been explored. METHODS: Controlled cortical injury was induced in both wild-type (WT) and TREM2 depletion (TREM2 KO) mice to simulate clinical TBI. COG1410 was used to upregulate TREM2, while PLX5622 and GSK2033 were used to deplete microglia and inhibit the liver X receptor (LXR), respectively. Immunofluorescence, Luxol fast blue staining, magnetic resonance imaging, transmission electron microscopy, and oil red O staining were employed to assess WMI after TBI. Neurological behaviour tests and electrophysiological recordings were utilized to evaluate cognitive functions following TBI. Microglial cell sorting and transcriptomic sequencing were utilized to identify alterations in microglial sterol metabolism-related genes, while western blot was conducted to validate the findings. RESULTS: TREM2 expressed highest at 3 days post-TBI and was predominantly localized to microglial cells within the white matter. Depletion of TREM2 worsened aberrant neurological behaviours, and this phenome...