DOI: 10.1007/s12640-016-9670-0 Pages: 204-217
Article Type: Original Article

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

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

2. Guangzhou Women and Children’s Medical Center

3. First Affiliated Hospital of Guangxi Medical University

4. United Family Healthcare Guangzhou Clinic

Correspondence to:
Zhi-Bin Yao
Email: yaozb_sysu@sina.com

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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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  • Accepted: Sep 15, 2016
  • Online: Nov 15, 2016
  • Revised: Aug 26, 2016

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