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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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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DOI: https://doi.org/10.1007/s12640-016-9670-0