National Key-Laboratory of Intelligent Tracing and Forecasting for Infectious Disease, NHC Key Laboratory of Medical Virology and Viral Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
Mol Neurobiol. 2024 Dec;61(12):9756-9775. doi: 10.1007/s12035-023-03511-8. Epub 2023 Aug 7.
Interleukin 3 (IL-3) plays an important role in hematopoiesis and immune regulation, brain IL-3/IL-3R signaling has been shown to involve in the physiological and pathological processes of a variety of neurodegenerative diseases, but its role in prion diseases is rarely described. Here, the changes of IL-3/IL-3R and its downstream signaling pathways in a scrapie-infected cell line and in the brains of several scrapie-infected rodent models were evaluated by various methods. Markedly decreased IL-3Rα were observed in the brains of scrapie-infected rodents at terminal stage and in the prion-infected cell model, which showed increased in the brain samples collected at early and middle stage of infection. The IL-3 levels were almost unchanged in the brains of scrapie-infected mice and in the prion-infected cell line. Morphological assays identified close co-localization of the increased IL-3Rα signals with NeuN- and Iba1-positive cells, whereas co-localization of IL-3 signals with NeuN- and GFAP-positive cells in the scrapie-infected brain tissues. Some downstream components of IL-3/IL-3R pathways, including JAK2-STAT5 and PI3K/AKT/mTOR pathways, were downregulated in the brains of scrapie-infected rodents at terminal stage and in the prion-infected cells. Stimulation of recombinant IL-3 on the cultured cells showed prion that the prion-infected cells displayed markedly more reluctant responses of JAK2-STAT5 and PI3K/AKT/mTOR pathways than the normal partner cells. These data suggest that although prion infection or PrP accumulation in brain tissues does not affect IL-3 expression, it significantly downregulates IL-3R levels, thereby inhibiting the downstream pathways of IL-3/IL-3R and blocking the neuroregulatory and neuroprotective activities of IL-3.
白细胞介素 3（IL-3）在造血和免疫调节中发挥重要作用，脑内 IL-3/IL-3R 信号转导已被证明参与多种神经退行性疾病的生理和病理过程，但它在朊病毒病中的作用很少被描述。在这里，通过各种方法评估了白细胞介素 3/白细胞介素 3 受体（IL-3R）及其下游信号通路在感染羊瘙痒病细胞系和几种感染羊瘙痒病啮齿动物模型中的变化。在感染羊瘙痒病的啮齿动物的大脑的终末期和朊病毒感染的细胞模型中观察到明显减少的 IL-3Rα，而在感染早期和中期的大脑样本中显示增加。在感染羊瘙痒病的小鼠的大脑和感染朊病毒的细胞系中，IL-3 水平几乎不变。形态学检测鉴定出增加的 IL-3Rα 信号与 NeuN 和 Iba1 阳性细胞密切共定位，而在感染羊瘙痒病的脑组织中，IL-3 信号与 NeuN 和 GFAP 阳性细胞共定位。IL-3/IL-3R 途径的一些下游成分，包括 JAK2-STAT5 和 PI3K/AKT/mTOR 途径，在感染羊瘙痒病的啮齿动物的大脑终末期和感染朊病毒的细胞中下调。重组 IL-3 对培养细胞的刺激表明，朊病毒感染细胞对 JAK2-STAT5 和 PI3K/AKT/mTOR 途径的反应明显比正常的配对细胞更不情愿。这些数据表明，尽管朊病毒感染或脑组织中 PrP 积累不影响 IL-3 的表达，但它显著下调 IL-3R 水平，从而抑制 IL-3/IL-3R 的下游途径，并阻断 IL-3 的神经调节和神经保护活性。
