美国布莱根妇女医院和哈佛医学院Vijay K. Kuchroo小组的最新研究探明了免疫检查点TIM-3调节小胶质细胞和阿尔茨海默病。该研究于2025年4月9日发表于国际一流学术期刊《自然》杂志上。

课题组在小鼠模型中证明TGFβ信号可诱导小胶质细胞中TIM-3的表达。反过来，TIM-3通过其羧基末端尾部与SMAD2和TGFBR2相互作用，通过促进TGFBR介导的SMAD2磷酸化来增强TGFβ信号传导，这一过程维持小胶质细胞的稳态。小胶质细胞中Havcr2基因缺失导致吞噬活性增加，基因表达谱与神经退行性小胶质细胞表型（MGnD）一致，也被称为疾病相关小胶质细胞（DAM）。

此外，小胶质细胞靶向缺失Havcr2可改善5×FAD小鼠（阿尔茨海默病的转基因模型）的认知障碍并减少淀粉样蛋白-β病理。单核RNA测序显示，在Havcr2缺陷5×FAD小鼠中存在MGnD小胶质细胞亚群，其特征是促吞噬和抗炎基因表达增加，促炎基因表达减少。在Havcr2缺陷5×FAD小鼠的大多数小胶质细胞中，单细胞RNA测序数据证实了这些转录组学变化。他们的发现揭示了TIM-3通过TGFβ信号介导小胶质细胞稳态，并强调了靶向小胶质细胞TIM-3治疗阿尔茨海默病的潜力。

据介绍，小胶质细胞是大脑中的常驻免疫细胞，在神经发育和神经炎症中起着关键作用。本研究探讨了免疫检查点分子TIM-3（由HAVCR2编码）在小胶质细胞中的功能。TIM-3最近被确定为迟发性阿尔茨海默病的遗传风险因素，它可以诱导T细胞耗竭。然而，其在脑小胶质细胞中的具体功能尚不清楚。

附：英文原文

Title: Immune checkpoint TIM-3 regulates microglia and Alzheimer’s disease

Author: Kimura, Kimitoshi, Subramanian, Ayshwarya, Yin, Zhuoran, Khalilnezhad, Ahad, Wu, Yufan, He, Danyang, Dixon, Karen O., Chitta, Udbhav Kasyap, Ding, Xiaokai, Adhikari, Niraj, Guzchenko, Isabell, Zhang, Xiaoming, Tang, Ruihan, Pertel, Thomas, Myers, Samuel A., Aastha, Aastha, Nomura, Masashi, Eskandari-Sedighi, Ghazaleh, Singh, Vasundhara, Liu, Lei, Lambden, Conner, Kleemann, Kilian L., Gupta, Neha, Barry, Jen-Li, Durao, Ana, Cheng, Yiran, Silveira, Sebastian, Zhang, Huiyuan, Suhail, Aamir, Delorey, Toni, Rozenblatt-Rosen, Orit, Freeman, Gordon J., Selkoe, Dennis J., Weiner, Howard L., Blurton-Jones, Mathew, Cruchaga, Carlos, Regev, Aviv, Suv, Mario L., Butovsky, Oleg, Kuchroo, Vijay K.

Issue&Volume: 2025-04-09

Abstract: Microglia are the resident immune cells in the brain and have pivotal roles in neurodevelopment and neuroinflammation1,2. This study investigates the function of the immune-checkpoint molecule TIM-3 (encoded by HAVCR2) in microglia. TIM-3 was recently identified as a genetic risk factor for late-onset Alzheimer’s disease3, and it can induce Tcell exhaustion4. However, its specific function in brain microglia remains unclear. We demonstrate in mouse models that TGFβ signalling induces TIM-3 expression in microglia. In turn, TIM-3 interacts with SMAD2 and TGFBR2 through its carboxy-terminal tail, which enhances TGFβ signalling by promoting TGFBR-mediated SMAD2 phosphorylation, and this process maintains microglial homeostasis. Genetic deletion of Havcr2 in microglia leads to increased phagocytic activity and a gene-expression profile consistent with the neurodegenerative microglial phenotype (MGnD), also referred to as disease-associated microglia (DAM). Furthermore, microglia-targeted deletion of Havcr2 ameliorates cognitive impairment and reduces amyloid-β pathology in 5×FAD mice (a transgenic model of Alzheimer’s disease). Single-nucleus RNA sequencing revealed a subpopulation of MGnD microglia in Havcr2-deficient 5×FAD mice characterized by increased pro-phagocytic and anti-inflammatory gene expression alongside reduced pro-inflammatory gene expression. These transcriptomic changes were corroborated by single-cell RNA sequencing data across most microglial clusters in Havcr2-deficient 5×FAD mice. Our findings reveal that TIM-3 mediates microglia homeostasis through TGFβ signalling and highlight the therapeutic potential of targeting microglial TIM-3 in Alzheimer’s disease.

DOI: 10.1038/s41586-025-08852-z

Source: https://www.nature.com/articles/s41586-025-08852-z