National Key-Laboratory of Intelligent Tracing and Forecasting for Infectious Disease, NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China.
North China University of Science and Technology, Tangshan 063210 China.
ACS Chem Neurosci. 2023 Oct 18;14(20):3772-3793. doi: 10.1021/acschemneuro.3c00344. Epub 2023 Sep 28.
Galectin 3 (Gal-3) is one of the major elements for activating microglia and mediating neuroinflammation in some types of neurodegenerative diseases. However, its role in the pathogenesis of prion disease is seldom addressed. In this study, markedly increased brain Gal-3 was identified in three scrapie-infected rodent models at the terminal stage. The increased Gal-3 was mainly colocalized with the activated microglia. Coincidental with the increased brain Gal-3 in prion-infected animals, the expression of brain trigger receptor expressed in myeloid cell 2 (TREM2), one of the Gal-3 receptors, and some components in the downstream pathway also significantly increased, whereas Toll-like receptor 4 (TLR4), another Gal-3 receptor, and the main components in its downstream signaling were less changed. The increased Gal-3 signals were distributed at the areas with PrP deposit but looked not to colocalize directly with PrP/PrP signals. Similar changing profiles of Gal-3, the receptors TREM2 and TLR4, as well as the proteins in the downstream pathways were also observed in prion-infected cell line SMB-S15. Removal of PrP replication in SMB-S15 cells reversed the upregulation of cellular Gal-3, TREM2, and the relevant proteins. Moreover, we presented data for interactions of Gal-3 with TREM2 and with TLR4 morphologically and molecularly in the cultured cells. Stimulation of prion-infected cells or their normal partner cells with recombinant mouse Gal-3 in vitro induced obvious responses for activation of TREM2 signaling and TLR4 signaling. Our data here strongly indicate that prion infection or PrP deposit induces remarkably upregulated brain Gal-3, which is actively involved in the microglia activation and neuroinflammation mainly via TREM2 signaling.
半乳糖凝集素 3（Gal-3）是激活小胶质细胞并介导某些类型神经退行性疾病中神经炎症的主要因素之一。然而，其在朊病毒病发病机制中的作用很少被涉及。在本研究中，在三种朊病毒感染的啮齿动物模型的终末期，明显增加了大脑中的 Gal-3。增加的 Gal-3 主要与激活的小胶质细胞共定位。与朊病毒感染动物大脑中 Gal-3 的增加一致，脑触发受体表达在髓样细胞 2（TREM2）的表达，Gal-3 的一种受体，以及下游途径中的一些成分也显著增加，而 Toll 样受体 4（TLR4），Gal-3 的另一种受体，以及其下游信号的主要成分变化较小。增加的 Gal-3 信号分布在有 PrP 沉积的区域，但看起来与 PrP/PrP 信号没有直接共定位。在朊病毒感染的 SMB-S15 细胞系中也观察到 Gal-3、受体 TREM2 和 TLR4 以及下游途径中的蛋白质的类似变化。在 SMB-S15 细胞中去除 PrP 复制逆转了细胞 Gal-3、TREM2 和相关蛋白的上调。此外，我们还在培养细胞中提供了 Gal-3 与 TREM2 以及与 TLR4 相互作用的形态学和分子学数据。体外用重组小鼠 Gal-3 刺激朊病毒感染的细胞或其正常的配对细胞可明显诱导 TREM2 信号和 TLR4 信号的激活。我们这里的数据强烈表明，朊病毒感染或 PrP 沉积诱导大脑中 Gal-3 的显著上调，Gal-3 通过 TREM2 信号积极参与小胶质细胞的激活和神经炎症。
