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Glucocorticoids Prevent Enterovirus 71 Capsid Protein VP1 Induced Calreticulin Surface Exposure by Alleviating Neuronal ER Stress

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Abstract

Severe hand-foot-and-mouth disease (HFMD) caused by Enterovirus 71 (EV71) always accompanies with inflammation and neuronal damage in the central nervous system (CNS). During neuronal injuries, cell surface-exposed calreticulin (Ecto-CRT) is an important mediator for primary phagocytosis of viable neurons by microglia. Our data confirmed that brainstem neurons underwent neuronophagia by glia in EV71-induced death cases of HFMD. EV71 capsid proteins VP1, VP2, VP3, or VP4 did not induce apoptosis of brainstem neurons. Interestingly, we found VP1-activated endoplasmic reticulum (ER) stress and autophagy could promote Ecto-CRT upregulation, but ER stress or autophagy alone was not sufficient to induce CRT exposure. Furthermore, we demonstrated that VP1-induced autophagy activation was mediated by ER stress. Meaningfully, we found dexamethasone treatment could attenuate Ecto-CRT upregulation by alleviating VP1-induced ER stress. Altogether, these findings identify VP1-promoted Ecto-CRT upregulation as a novel mechanism of EV71-induced neuronal cell damage and highlight the potential of the use of glucocorticoids to treat severe HFMD patients with CNS complications.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 31371130); the Special Foundation of Education Department of Guangdong Province, the Medical Scientific Research Foundation of Guangdong Province, China (No. 2013-159); the Foundation of Medical Science and Technology Research of Guangdong Province (No. A2016273); the Guangdong Provincial Department of Science and Technology, China (No. 2013B021800039 and 2012B031800012); the Natural Science Foundation of Guangdong Province, China (No. S2013010015018); the science and technology project (medical and health) of Guangzhou, China (No. 20131A011062); and the fund from Guangzhou Institute of Pediatrics/Guangzhou Women and Children’s Medical Center (No. 0160036).

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    1. Department of Anatomy Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China

      Dan-Dan Hu & Zhi-Bin Yao

    2. Guangzhou Women and Children’s Medical Center, Guangzhou, 510623, Guangdong, China

      Dan-Dan Hu, Jian-Ning Mai, Li-Ya He, Pei-Qing Li, Wen-Xiong Chen, Jian-Jiang Yan, Wei-Dong Zhu, Li Deng & Si-Da Yang

    3. First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China

      Dan Wei

    4. United Family Healthcare Guangzhou Clinic, Guangzhou, 510600, China

      Di-Hui Liu

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    Dan-Dan Hu, Jian-Ning Mai, and Li-Ya He have contributed equally to this work.

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    Hu, DD., Mai, JN., He, LY. et al. Glucocorticoids Prevent Enterovirus 71 Capsid Protein VP1 Induced Calreticulin Surface Exposure by Alleviating Neuronal ER Stress. Neurotox Res 31, 204–217 (2017). https://doi.org/10.1007/s12640-016-9670-0

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