中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (2): 434-438.doi: 10.4103/1673-5374.346468

• 原著:退行性病与再生 • 上一篇    下一篇

阿尔茨海默病治疗的新标靶：TREML2

  

  • 出版日期:2023-02-15 发布日期:2022-08-09

The Alzheimer’s disease-associated gene TREML2 modulates inflammation by regulating microglia polarization and NLRP3 inflammasome activation

Si-Yu Wang1, #, Xin-Xin Fu2, #, Rui Duan1, Bin Wei1, Hai-Ming Cao1, Yan E1, Shuai-Yu Chen1, Ying-Dong Zhang1, 2, *, Teng Jiang1, *   

  1. 1Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China; 2Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, China
  • Online:2023-02-15 Published:2022-08-09
  • Contact: Teng Jiang, MD, PhD, jiang_teng@njmu.edu.cn; Ying-Dong Zhang, MD, PhD, zhangyingdong@njmu.edu.cn.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, No. 81974156 (to TJ) and the Natural Science Foundation of Jiangsu Province, No. BK20201117 (to YDZ).

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摘要：

髓细胞触发受体样蛋白2基因（TREML2）是一个新发现的阿尔茨海默病（AD）的易感基因，它编码一个小胶质细胞炎症相关的受体。到目前为止，小胶质细胞TREML2在阿尔茨海默病条件下的神经炎症中的潜在作用仍不清楚。实验利用Western blot研究了阿尔茨海默病转基因模型APP/PS1小鼠大脑中TREML2水平在疾病进展过程中的动态变化。随后，采用脂多糖刺激原代小胶质细胞以及慢病毒介导的TREML2过表达和敲低策略，探讨小胶质细胞TREML2在阿尔茨海默病条件下神经炎症中的作用。用酶联免疫吸附法检测小胶质细胞培养液中炎症细胞因子白细胞介素1β、白细胞介素6和肿瘤坏死因子α的蛋白水平。以Western blot检测含NLR家族PYRIN域蛋白3（NLRP3）和小胶质细胞极化标志物诱导型一氧化氮合成酶、CD206和精氨酸酶1的蛋白水平。结果显示，在疾病发展过程中，APP/PS1小鼠脑中TREML2的蛋白水平逐渐增加。在初级小胶质细胞中，脂多糖刺激导致了炎症细胞因子的释放。TREML2过量表达后，脂多糖诱导的小胶质细胞释放的炎性细胞因子增强，TREML2敲低后则减弱。小胶质细胞M1型极化标志物诱导型一氧化氮合成酶的蛋白水平因脂多糖刺激而增加，并因TREML2的过表达而进一步增强，而因TREML2的敲低而得到改善。同时，原代小胶质细胞中M2型极化标志物CD206和ARG1的蛋白水平因TREML2过表达而降低，因TREML2敲低而升高。脂多糖增加了原代小胶质细胞中NLRP3的蛋白水平。脂多糖诱导的NLRP3的增加因TREML2过表达进一步提高，并被TREML2敲低所缓解。总之，实验证明TREML2通过调节小胶质细胞的极化和NLRP3炎症体的激活来调节炎症。这些发现揭示了TREML2调节小胶质细胞炎症的机制，因而TREML2可能成为阿尔茨海默病治疗的新标靶。

https://orcid.org/0000-0003-4170-1156 (Teng Jiang); https://orcid.org/0000-0001-7803-5367 (Ying-Dong Zhang)

Abstract: Triggering receptor expressed on myeloid cells-like 2 (TREML2) is a newly identified susceptibility gene for Alzheimer’s disease (AD). It encodes a microglial inflammation-associated receptor. To date, the potential role of microglial TREML2 in neuroinflammation in the context of AD remains unclear. In this study, APP/PS1 mice were used to investigate the dynamic changes of TREML2 levels in brain during AD progression. In addition, lipopolysaccharide (LPS)  stimulation of primary microglia as well as a lentivirus-mediated TREML2 overexpression and knockdown were employed to explore the role of TREML2 in neuroinflammation in the context of AD. Our results show that TREML2 levels gradually increased in the brains of APP/PS1 mice during disease progression. LPS stimulation of primary microglia led to the release of inflammatory cytokines including interleukin-1β, interleukin-6, and tumor necrosis factor-α in the culture medium. The LPS-induced microglial release of inflammatory cytokines was enhanced by TREML2 overexpression and was attenuated by TREML2 knockdown. LPS increased the levels of microglial M1-type polarization marker inducible nitric oxide synthase. This effect was enhanced by TREML2 overexpression and ameliorated by TREML2 knockdown. Furthermore, the levels of microglial M2-type polarization markers CD206 and ARG1 in the primary microglia were reduced by TREML2 overexpression and elevated by TREML2 knockdown. LPS stimulation increased the levels of NLRP3 in primary microglia. The LPS-induced increase in NLRP3 was further elevated by TREML2 overexpression and alleviated by TREML2 knockdown. In summary, this study provides the first evidence that TREML2 modulates inflammation by regulating microglial polarization and NLRP3 inflammasome activation. These findings reveal the mechanisms by which TREML2 regulates microglial inflammation and suggest that TREML2 inhibition may represent a novel therapeutic strategy for AD. 

Key words: Alzheimer’s disease, APP/PS1 mice, inflammatory cytokine, lipopolysaccharide, microglia, neuroinflammation, NLRP3 inflammasome, polarization, susceptibility gene, TREML2