Department of Neurosurgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
Mol Neurobiol. 2024 Jul;61(7):4649-4662. doi: 10.1007/s12035-023-03875-x. Epub 2023 Dec 19.
Previous studies have indicated that iron disorder, inflammation, and autophagy play an important role in traumatic brain injury (TBI). The triggering receptor expressed on myeloid cells 2 (TREM2), an immunoglobulin superfamily transmembrane receptor, is involved in inflammation. However, the role of TREM2 in modulating the microglia response in TBI has been rarely investigated. The present study aimed to investigate if the iron chelator deferoxamine (DFO) could ameliorate TBI through autophagy mediated by the TREM2. TBI was developed by the controlled cortical impact (CCI) mouse model and stretching of individual primary cortical microglia taken from the tissue of the rat brain. DFO was intraperitoneally used for intervention. Western blotting assay, qRT-PCR, TUNEL staining, immunofluorescence staining, confocal microscopy analysis, transmission electron microscopy, H&E staining, brain water content measurement, and the neurobehavioral assessments were performed. TREM2 expression was up-regulated in cortex of TBI mice model and in microglia stretching model, which was attenuated by DFO. After the mice were subjected to CCI, DFO treatment significantly up-regulated the protein levels of autophagy compared with the TBI group at 3 days and caused an increase of autophagic vacuoles. Treatment with DFO reduced TBI-induced cell apoptosis, cerebral edema, neuroinflammation, and motor function impairment in mice, at least partly via the mTOR signaling pathway that facilitates the TREM2 activity. The results indicated that the maintenance of iron homeostasis by DFO plays neuroprotection by modulating the inflammatory response to TBI through TREM2-mediated autophagy. This study suggested that TREM2-mediated autophagy might be a potential target for therapeutic intervention in TBI.
先前的研究表明，铁代谢紊乱、炎症和自噬在创伤性脑损伤（TBI）中起着重要作用。髓样细胞触发受体 2（TREM2）是免疫球蛋白超家族跨膜受体，参与炎症反应。然而，TREM2 在调节 TBI 中小胶质细胞反应中的作用尚未得到广泛研究。本研究旨在探讨铁螯合剂去铁胺（DFO）是否可以通过 TREM2 介导的自噬来改善 TBI。采用皮质冲击（CCI）小鼠模型和大鼠脑组织原代皮质小胶质细胞拉伸建立 TBI 模型，腹腔内给予 DFO 干预。采用 Western blot 检测、qRT-PCR、TUNEL 染色、免疫荧光染色、共聚焦显微镜分析、透射电镜、H&E 染色、脑水含量测定和神经行为学评估。TREM2 表达在 TBI 小鼠模型和小胶质细胞拉伸模型的皮质中上调，DFO 可减弱其表达。CCI 后，与 TBI 组相比，DFO 处理组在 3 天时明显上调了自噬蛋白水平，并导致自噬小泡增加。DFO 处理减轻了 TBI 诱导的细胞凋亡、脑水肿、神经炎症和小鼠运动功能障碍，至少部分通过促进 TREM2 活性的 mTOR 信号通路。结果表明，DFO 通过调节 TREM2 介导的自噬来维持铁代谢平衡，从而发挥神经保护作用。本研究提示，TREM2 介导的自噬可能是 TBI 治疗干预的潜在靶点。
