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

作者全名：Li, Zhao; Yu, Shenghui; Li, Lin; Zhou, Chao; Wang, Lin; Tang, Shuang; Gu, Nina; Zhang, Zhaosi; Huang, Zhijian; Chen, Hong; Tang, Wei; Wang, Yingwen; Yang, Xiaomin; Sun, Xiaochuan; Yan, Jin

作者地址：[Li, Zhao; Wang, Lin; Tang, Shuang; Gu, Nina; Zhang, Zhaosi; Huang, Zhijian; Chen, Hong; Tang, Wei; Wang, Yingwen; Yang, Xiaomin; Sun, Xiaochuan; Yan, Jin] Chongqing Med Univ, Affiliated Hosp 1, Dept Neurosurg, 1 Youyi Rd, Chongqing 400016, Peoples R China; [Li, Zhao; Yu, Shenghui; Zhou, Chao] Chengdu First Peoples Hosp, Emergency Dept, Chengdu, Peoples R China; [Li, Lin] Chongqing Univ, Canc Hosp, Dept Neurosurg, Chongqing, Peoples R China; [Wang, Lin] Nanchong Cent Hosp, Clin Med Coll 2, North Sichuan Med Coll, Dept Neurosurg, Nanchong, Peoples R China; [Tang, Shuang] Suining Cent Hosp, Dept Neurosurg, Suining, Peoples R China

通信作者：Yang, XM; Sun, XC; Yan, J (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Neurosurg, 1 Youyi Rd, Chongqing 400016, Peoples R China.

来源：CLINICAL AND TRANSLATIONAL MEDICINE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001206756600001

JCR分区：Q1

影响因子：7.9

年份：2024

卷号：14

期号：4

开始页：　

结束页：　

文献类型：Article

关键词：DHCR24; LXR; microglia; oligodendrocyte precursor cells; oligodendrocytes; sterol metabolism; traumatic brain injury; TREM2; white matter injury

摘要：BackgroundWhite 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.MethodsControlled 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.ResultsTREM2 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 phenomenon was mediated by the exacerbation of WMI, reduced renewal of oligodendrocytes, and impaired phagocytosis ability of microglia after TBI. Subsequently, the upregulation of TREM2 alleviated WMI, promoted oligodendrocyte regeneration, and ultimately facilitated the recovery of neurological behaviours after TBI. Finally, the expression of DHCR24 increased in TREM2 KO mice after TBI. Interestingly, TREM2 inhibited DHCR24 and upregulated members of the LXR pathway. Moreover, LXR inhibition could partially reverse the effects of TREM2 upregulation on electrophysiological activities.ConclusionsWe demonstrate that TREM2 has the potential to alleviate WMI following TBI, possibly through the DHCR24/LXR pathway in microglia. TREM2 depletion exacerbates WMI and cognitive deficits after TBI. TREM2 upregulation alleviates WMI and promotes cognition recovery after TBI. DHCR24 is upregulated after TBI in TREM2 KO mice and can be inhibited by TREM2 upregulation. TREM2 may alleviate WMI after TBI by regulating DHCR24/LXR pathway in microglia. image

基金机构：Sichuan Province Medical Youth Innovation Research Project Plan; Chongqing Key Laboratory of Neurology (Chongqing, China); National Natural Science Foundation of China [82071397]; [Q23087]; [82102316]; [CSTB2022BSXM-JCX0042]

基金资助正文：We would like to thank the service provided by the Chongqing Key Laboratory of Neurology (Chongqing, China). This work was supported by Sichuan Province Medical Youth Innovation Research Project Plan, No. Q23087 to Dr. Zhao Li, National Natural Science Foundation of China, No. 82102316 to Dr. Huang, Chongqing Doctor's 'Direct Train' Research Project, No. CSTB2022BSXM-JCX0042 to Dr. Chen, and National Natural Science Foundation of China, No. 82071397 to Dr. Sun.