Microglial TREM2 promotes phagocytic clearance of damaged neurons after status epilepticus

IF 8.8 2区 医学 Q1 IMMUNOLOGY
Dale B. Bosco , Vaclav Kremen , Koichiro Haruwaka , Shunyi Zhao , Lingxiao Wang , Blake A. Ebner , Jiaying Zheng , Manling Xie , Aastha Dheer , Jadyn F. Perry , Abhijeet Barath , Aivi T. Nguyen , Gregory A. Worrell , Long-Jun Wu
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引用次数: 0

Abstract

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.
小胶质细胞 TREM2 促进对癫痫状态后受损神经元的吞噬清除。
在中枢神经系统中,髓系细胞上表达的触发受体 2(TREM2)专门由小胶质细胞表达,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 在阿尔茨海默病和肌萎缩侧索硬化症等神经退行性疾病中发挥着重要作用。然而,人们对 TREM2 如何影响癫痫发生过程中的小胶质细胞功能知之甚少。为了研究这个问题,我们利用雄性 TREM2 基因敲除(KO)小鼠在小鼠杏仁核内凯尼酸癫痫模型中进行研究。脑电图分析、免疫细胞化学和 RNA 测序显示,TREM2 的缺失会显著促进癫痫发作诱发的病理变化。我们发现,TREM2 KO会增加急性癫痫状态的严重程度和慢性局灶性癫痫特征性的自发性复发性发作次数。小胶质细胞对受损神经元的吞噬清除能力也会因 TREM2 KO 而受损,吞噬活性的降低与自发性癫痫发作的增加有关。对因耐药性颞叶癫痫而接受手术切除的患者的人体组织进行的分析也显示,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史呈负相关。这些结果表明,小胶质细胞 TREM2 和吞噬活性对致痫病理学非常重要。
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来源期刊
CiteScore
29.60
自引率
2.00%
发文量
290
审稿时长
28 days
期刊介绍: Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals. As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.
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