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

• Published in: Neurotoxicity research Vol. 31; no. 2; pp. 204 - 217
• Main Authors: Hu, Dan-Dan, Mai, Jian-Ning, He, Li-Ya, Li, Pei-Qing, Chen, Wen-Xiong, Yan, Jian-Jiang, Zhu, Wei-Dong, Deng, Li, Wei, Dan, Liu, Di-Hui, Yang, Si-Da, Yao, Zhi-Bin
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2017
• Subjects: Animals; Autophagy - drug effects; Autophagy - physiology; Biomedical and Life Sciences; Biomedicine; Brain Stem - drug effects; Brain Stem - physiopathology; Calreticulin - metabolism; Capsid Proteins - toxicity; Cell Biology; Cells, Cultured; Dexamethasone - pharmacology; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - physiology; Female; Humans; Male; Neurobiology; Neurochemistry; Neurology; Neurons - physiology; Neurosciences; Original Article; Phagocytosis - drug effects; Phagocytosis - physiology; Pharmacology/Toxicology; Rats; Up-Regulation; Viral Structural Proteins - toxicity; Enterovirus 71; Calreticulin; Hand-foot-and-mouth disease; Glucocorticoids
• ISSN: 1029-8428; 1476-3524
• DOI: 10.1007/s12640-016-9670-0

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.