TREM2 activation alleviates neural damage via Akt/CREB/BDNF signalling after traumatic brain injury in mice

作者全名："Yan, Jin; Zhang, Yuan; Wang, Lin; Li, Zhao; Tang, Shuang; Wang, Yingwen; Gu, Nina; Sun, Xiaochuan; Li, Lin"

作者地址："[Yan, Jin; Wang, Lin; Li, Zhao; Tang, Shuang; Wang, Yingwen; Gu, Nina; Sun, Xiaochuan; Li, Lin] Chongqing Med Univ, Affiliated Hosp 1, Dept Neurosurg, 1 Youyi Rd, Chongqing 400016, Peoples R China; [Zhang, Yuan; Wang, Lin] Nanchong Cent Hosp, Clin Med Coll North Sichuan Med Coll 2, Dept Neurosurg, Nanchong, Peoples R China; [Li, Zhao] Chengdu Integrated TCM & Western Med Hosp, Dept Neurosurg, Chengdu, Peoples R China; [Tang, Shuang] Suining Cent Hosp, Dept Neurosurg, Suining, Peoples R China; [Li, Lin] Chongqing Univ Canc Hosp, Dept Neurooncol, Chongqing, Peoples R China; [Li, Lin] Affiliated Hosp, North Sichuan Med Coll, Dept Neurosurg, Nanchong, Peoples R China"

通信作者："Sun, XC; Li, L (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Neurosurg, 1 Youyi Rd, Chongqing 400016, Peoples R China.; Li, L (通讯作者)，Chongqing Univ Canc Hosp, Dept Neurooncol, Chongqing, Peoples R China.; Li, L (通讯作者)，Affiliated Hosp, North Sichuan Med Coll, Dept Neurosurg, Nanchong, Peoples R China."

来源：JOURNAL OF NEUROINFLAMMATION

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:000893929200002

JCR分区：Q1

影响因子：9.3

年份：2022

卷号：19

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Traumatic brain injury; TREM2; Neuroinflammation; Neural apoptosis; Cognitive deficits

摘要："Background: Neuroinflammation is one of the most important processes in secondary injury after traumatic brain injury (TBI). Triggering receptor expressed on myeloid cells 2 (TREM2) has been proven to exert neuroprotective effects in neurodegenerative diseases and stroke by modulating neuroinflammation, and promoting phagocytosis and cell survival. However, the role of TREM2 in TBI has not yet been elucidated. In this study, we are the first to use COG1410, an agonist of TREM2, to assess the effects of TREM2 activation in a murine TBI model. Methods: Adult male wild-type (WT) C57BL/6 mice and adult male TREM2 KO mice were subjected to different treatments. TBI was established by the controlled cortical impact (CCI) method. COG1410 was delivered 1 h after CCI via tail vein injection. Western blot analysis, immunofluorescence, laser speckle contrast imaging (LSCI), neurological behaviour tests, brain electrophysiological monitoring, Evans blue assays, magnetic resonance imaging (MRI), and brain water content measurement were performed in this study. Results: The expression of endogenous TREM2 peaked at 3 d after CCI, and it was mainly expressed on microglia and neurons. We found that COG1410 improved neurological functions within 3 d, as well as neurological functions and brain electrophysiological activity at 2 weeks after CCI. COG1410 exerted neuroprotective effects by inhibiting neutrophil infiltration and microglial activation, and suppressing neuroinflammation after CCI. In addition, COG1410 treatment alleviated blood brain barrier (BBB) disruption and brain oedema; furthermore, COG1410 promoted cerebral blood flow (CBF) recovery at traumatic injury sites after CCI. In addition, COG1410 suppressed neural apoptosis at 3 d after CCI. TREM2 activation upregulated p-Akt, p-CREB, BDNF, and Bcl-2 and suppressed TNF-alpha, IL-1 beta, Bax, and cleaved caspase-3 at 3 d after CCI. Moreover, TREM2 knockout abolished the effects of COG1410 on vascular phenotypes and microglial states. Finally, the neuroprotective effects of COG1410 were suppressed by TREM2 depletion. Conclusions: Altogether, we are the first to demonstrate that TREM2 activation by COG1410 alleviated neural damage through activation of Akt/CREB/BDNF signalling axis in microglia after CCI. Finally, COG1410 treatment improved neurological behaviour and brain electrophysiological activity after CCI."

基金机构：National Natural Science Foundation of China; Bureau of Science and Technology Nanchong City [82071397]; [22SXQT0048]

基金资助正文："The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this study was spon-sored by the National Natural Science Foundation of China, No. 82071397 to Dr Sun, and the Bureau of Science and Technology Nanchong City, No. 22SXQT0048 to Dr Zhang."