Bosco Dale B, Kremen Vaclav, Haruwaka Koichiro, Zhao Shunyi, Wang Lingxiao, Ebner Blake A, Zheng Jiaying, Xie Manling, Dheer Aastha, Perry Jadyn F, Barath Abhijeet, Nguyen Aivi T, Worrell Gregory A, Wu Long-Jun
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Center for Neuroimmunology and Glial Biology, Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
Brain Behav Immun. 2025 Jan;123:540-555. doi: 10.1016/j.bbi.2024.09.034. Epub 2024 Sep 29.
In the central nervous system, triggering receptor expressed on myeloid cells 2 (TREM2) is exclusively expressed by microglia and is critical for microglial proliferation, migration, and phagocytosis. Microglial TREM2 plays an important role in neurodegenerative diseases, such as Alzheimer's disease and amyotrophic lateral sclerosis. However, little is known about how TREM2 affects microglial function within epileptogenesis. To investigate this, we utilized male TREM2 knockout (KO) mice within the intra-amygdala kainic acid seizure model. Electroencephalographic analysis, immunocytochemistry, and RNA sequencing revealed that TREM2 deficiency significantly promoted seizure-induced pathology. We found that TREM2 KO increased both the severity of acute status epilepticus and the number of spontaneous recurrent seizures characteristic of chronic focal epilepsy. Phagocytic clearance of damaged neurons by microglia was also impaired by TREM2 KO and reduced phagocytic activity correlated with increased spontaneous seizures. Analysis of human tissue from patients who underwent surgical resection for drug resistant temporal lobe epilepsy also showed a negative correlation between expression of the microglial phagocytic marker CD68 and focal to bilateral tonic-clonic generalized seizure history. These results indicate that microglial TREM2 and phagocytic activity are important to epileptogenic pathology.
在中枢神经系统中，髓系细胞触发受体2（TREM2）仅由小胶质细胞表达，对小胶质细胞的增殖、迁移和吞噬作用至关重要。小胶质细胞TREM2在神经退行性疾病，如阿尔茨海默病和肌萎缩侧索硬化症中发挥重要作用。然而，关于TREM2如何在癫痫发生过程中影响小胶质细胞功能，人们知之甚少。为了研究这一点，我们在杏仁核内注射 kainic 酸癫痫模型中使用了雄性TREM2基因敲除（KO）小鼠。脑电图分析、免疫细胞化学和RNA测序显示，TREM2缺陷显著促进了癫痫发作诱导的病理变化。我们发现，TREM2基因敲除增加了急性癫痫持续状态的严重程度以及慢性局灶性癫痫特有的自发性反复癫痫发作的次数。小胶质细胞对受损神经元的吞噬清除也因TREM2基因敲除而受损，吞噬活性降低与自发性癫痫发作增加相关。对因耐药性颞叶癫痫接受手术切除的患者的人体组织分析也显示，小胶质细胞吞噬标记物CD68的表达与局灶性至双侧强直阵挛性全身性癫痫发作病史之间呈负相关。这些结果表明，小胶质细胞TREM2和吞噬活性对癫痫发生病理过程很重要。
