Inhibition of autophagy and chemokine induction by sphingosine 1-phosphate receptor 1 through NF-κB signaling in human pulmonary endothelial cells infected with influenza A viruses

Lan Wang, Hao Jiang, Si Mei Shen, Chun Xia Wen, Zheng Xing, Yi Shi

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4 Scopus citations

Abstract

Endothelial cells have been considered the central regulators of cytokine storm in the respiratory system during influenza virus infection. Studies have found that elevated autophagy could be an essential component of viral pathogenesis in influenza infection. However, few studies have been performed to examine whether autophagy occurs in human pulmonary endothelial cells (HPMECs). In addition, specific mechanisms about how inflammatory responses are regulated in the endothelial cells remain unclear. We hypothesized that infection of influenza A viruses subtypes H1N1 and H9N2 triggered autophagy, which played an important role in the induction of proinflammatory cytokines, both in human lung epithelial A549 cells and in HPMECs. In this report, we showed our evidence that blockage of autophagy significantly inhibited influenza virus-induced proinflammatory responses and suppressed viral replication. Our data indicated that the inhibition of the cytokine response and viral replication was affected by increasing the expression of endothelial sphingosine 1-phosphate receptor 1 (S1PR1), which might be through the regulation of NF-κB signaling. Overexpression of S1PR1 decreased p65 phosphorylation and translocation into the nucleus. Furthermore, we demonstrated that S1PR1 stimulation inhibited Akt-mTOR signaling, which might contribute to activation of autophagy in HPMECs. Thus, our study provides knowledge crucial to better understanding novel mechanisms underlying the S1PR1-medi-ated attenuation of cytokine amplification in the pulmonary system during influenza virus infection.

Original languageEnglish (US)
Article numbere0205344
JournalPloS one
Volume13
Issue number10
DOIs
StatePublished - Oct 2018

Bibliographical note

Funding Information:
This project was supported by National Natural Science Foundation of China (81470206, to Dr. Yi Shi) and by National Natural Science Foundation of Jiangsu Province, China (BK20151372, to Dr. Yi Shi). Zheng Xing was supported by the Minnesota Department of Agriculture Award (UMN Response to AI; Award #CON000000058786-00056110 & 00056111) and by National Natural Science Foundation of China (Grant No. 81571993). The funder did not have any role in the experiment design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Yuwen Rui, Ye Hong, and Binchan He for their technical assistance. We are grateful to Dr Jiwu Wei for providing us with the plasmid pGFP-LC3 and to Richard Shi, Jerome Gali-cia, and Irfan Qaisar for their help in editing the manuscript. This project was supported by National Natural Science Foundation of China (81470206, to Dr. Yi Shi) and by National Natural Science Foundation of Jiangsu Province, China (BK20151372, to Dr. Yi Shi). Zheng Xing was supported by the Minnesota Department of Agriculture Award (UMN Response to AI; Award #CON000000058786-00056110 & 00056111) and by National Natural Science Foundation of China (Grant No. 81571993).

Publisher Copyright:
Copyright: © 2018 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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