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Abnormal Changes of IL3/IL3R and Its Downstream Signaling Pathways in the Prion-Infected Cell Line and in the Brains of Scrapie-Infected Rodents

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Abstract

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 PrPSc 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.

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Data Availability

The datasets generated for this study are available on request to the corresponding.

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Funding

This work was supported by SKLID Development Grant (2021SKLID504, 2019SKLID401, 2019SKLID603).

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Author notes

  1. Xiao-Xi Jia and Cao Chen contributed equally to this work.

Authors and Affiliations

  1. 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

    Xiao-Xi Jia, Cao Chen, Chao Hu, Zhi-Yue Chao, Wei-Wei Zhang, Yue-Zhang Wu, Qin Fan, Ru-Han A, Xin Liu, Kang Xiao, Qi Shi & Xiao-Ping Dong

  2. Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China

    Cao Chen & Xiao-Ping Dong

  3. Xuanwu Hospital Capital Medical University, Beijing, China

    Chao Hu

  4. North China University of Science and Technology, Tangshan, China

    Wei-Wei Zhang

  5. China Academy of Chinese Medical Sciences, Beijing, China

    Qi Shi & Xiao-Ping Dong

  6. Shanghai Institute of Infectious Disease and Biosafety, Shanghai, China

    Xiao-Ping Dong

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  1. Xiao-Xi Jia
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Contributions

XXJ and CC contributed to study design, performed assays and data analysis, and prepared the manuscript. CH, ZYC, and WWZ assisted with the assays of cultured cells. WYZ, QF, RHA, and XL assisted with WB and IFA analysis assays. KX and QS assisted with statistical analysis. CC and XPD contributed to design, study concept, and manuscript preparation.

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Correspondence to Cao Chen or Xiao-Ping Dong.

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Jia, XX., Chen, C., Hu, C. et al. Abnormal Changes of IL3/IL3R and Its Downstream Signaling Pathways in the Prion-Infected Cell Line and in the Brains of Scrapie-Infected Rodents. Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03511-8

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