Cargando…

The Myeloid LSECtin Is a DAP12-Coupled Receptor That Is Crucial for Inflammatory Response Induced by Ebola Virus Glycoprotein

Fatal Ebola virus infection is characterized by a systemic inflammatory response similar to septic shock. Ebola glycoprotein (GP) is involved in this process through activating dendritic cells (DCs) and macrophages. However, the mechanism is unclear. Here, we showed that LSECtin (also known as CLEC4...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhao, Dianyuan, Han, Xintao, Zheng, Xuexing, Wang, Hualei, Yang, Zaopeng, Liu, Di, Han, Ke, Liu, Jing, Wang, Xiaowen, Yang, Wenting, Dong, Qingyang, Yang, Songtao, Xia, Xianzhu, Tang, Li, He, Fuchu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778874/
https://www.ncbi.nlm.nih.gov/pubmed/26943817
http://dx.doi.org/10.1371/journal.ppat.1005487
_version_ 1782419543420829696
author Zhao, Dianyuan
Han, Xintao
Zheng, Xuexing
Wang, Hualei
Yang, Zaopeng
Liu, Di
Han, Ke
Liu, Jing
Wang, Xiaowen
Yang, Wenting
Dong, Qingyang
Yang, Songtao
Xia, Xianzhu
Tang, Li
He, Fuchu
author_facet Zhao, Dianyuan
Han, Xintao
Zheng, Xuexing
Wang, Hualei
Yang, Zaopeng
Liu, Di
Han, Ke
Liu, Jing
Wang, Xiaowen
Yang, Wenting
Dong, Qingyang
Yang, Songtao
Xia, Xianzhu
Tang, Li
He, Fuchu
author_sort Zhao, Dianyuan
collection PubMed
description Fatal Ebola virus infection is characterized by a systemic inflammatory response similar to septic shock. Ebola glycoprotein (GP) is involved in this process through activating dendritic cells (DCs) and macrophages. However, the mechanism is unclear. Here, we showed that LSECtin (also known as CLEC4G) plays an important role in GP-mediated inflammatory responses in human DCs. Anti-LSECtin mAb engagement induced TNF-α and IL-6 production in DCs, whereas silencing of LSECtin abrogated this effect. Intriguingly, as a pathogen-derived ligand, Ebola GP could trigger TNF-α and IL-6 release by DCs through LSECtin. Mechanistic investigations revealed that LSECtin initiated signaling via association with a 12-kDa DNAX-activating protein (DAP12) and induced Syk activation. Mutation of key tyrosines in the DAP12 immunoreceptor tyrosine-based activation motif abrogated LSECtin-mediated signaling. Furthermore, Syk inhibitors significantly reduced the GP-triggered cytokine production in DCs. Therefore, our results demonstrate that LSECtin is required for the GP-induced inflammatory response, providing new insights into the EBOV-mediated inflammatory response.
format Online
Article
Text
id pubmed-4778874
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-47788742016-03-23 The Myeloid LSECtin Is a DAP12-Coupled Receptor That Is Crucial for Inflammatory Response Induced by Ebola Virus Glycoprotein Zhao, Dianyuan Han, Xintao Zheng, Xuexing Wang, Hualei Yang, Zaopeng Liu, Di Han, Ke Liu, Jing Wang, Xiaowen Yang, Wenting Dong, Qingyang Yang, Songtao Xia, Xianzhu Tang, Li He, Fuchu PLoS Pathog Research Article Fatal Ebola virus infection is characterized by a systemic inflammatory response similar to septic shock. Ebola glycoprotein (GP) is involved in this process through activating dendritic cells (DCs) and macrophages. However, the mechanism is unclear. Here, we showed that LSECtin (also known as CLEC4G) plays an important role in GP-mediated inflammatory responses in human DCs. Anti-LSECtin mAb engagement induced TNF-α and IL-6 production in DCs, whereas silencing of LSECtin abrogated this effect. Intriguingly, as a pathogen-derived ligand, Ebola GP could trigger TNF-α and IL-6 release by DCs through LSECtin. Mechanistic investigations revealed that LSECtin initiated signaling via association with a 12-kDa DNAX-activating protein (DAP12) and induced Syk activation. Mutation of key tyrosines in the DAP12 immunoreceptor tyrosine-based activation motif abrogated LSECtin-mediated signaling. Furthermore, Syk inhibitors significantly reduced the GP-triggered cytokine production in DCs. Therefore, our results demonstrate that LSECtin is required for the GP-induced inflammatory response, providing new insights into the EBOV-mediated inflammatory response. Public Library of Science 2016-03-04 /pmc/articles/PMC4778874/ /pubmed/26943817 http://dx.doi.org/10.1371/journal.ppat.1005487 Text en © 2016 Zhao et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
Zhao, Dianyuan
Han, Xintao
Zheng, Xuexing
Wang, Hualei
Yang, Zaopeng
Liu, Di
Han, Ke
Liu, Jing
Wang, Xiaowen
Yang, Wenting
Dong, Qingyang
Yang, Songtao
Xia, Xianzhu
Tang, Li
He, Fuchu
The Myeloid LSECtin Is a DAP12-Coupled Receptor That Is Crucial for Inflammatory Response Induced by Ebola Virus Glycoprotein
title The Myeloid LSECtin Is a DAP12-Coupled Receptor That Is Crucial for Inflammatory Response Induced by Ebola Virus Glycoprotein
title_full The Myeloid LSECtin Is a DAP12-Coupled Receptor That Is Crucial for Inflammatory Response Induced by Ebola Virus Glycoprotein
title_fullStr The Myeloid LSECtin Is a DAP12-Coupled Receptor That Is Crucial for Inflammatory Response Induced by Ebola Virus Glycoprotein
title_full_unstemmed The Myeloid LSECtin Is a DAP12-Coupled Receptor That Is Crucial for Inflammatory Response Induced by Ebola Virus Glycoprotein
title_short The Myeloid LSECtin Is a DAP12-Coupled Receptor That Is Crucial for Inflammatory Response Induced by Ebola Virus Glycoprotein
title_sort myeloid lsectin is a dap12-coupled receptor that is crucial for inflammatory response induced by ebola virus glycoprotein
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778874/
https://www.ncbi.nlm.nih.gov/pubmed/26943817
http://dx.doi.org/10.1371/journal.ppat.1005487
work_keys_str_mv AT zhaodianyuan themyeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT hanxintao themyeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT zhengxuexing themyeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT wanghualei themyeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT yangzaopeng themyeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT liudi themyeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT hanke themyeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT liujing themyeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT wangxiaowen themyeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT yangwenting themyeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT dongqingyang themyeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT yangsongtao themyeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT xiaxianzhu themyeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT tangli themyeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT hefuchu themyeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT zhaodianyuan myeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT hanxintao myeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT zhengxuexing myeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT wanghualei myeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT yangzaopeng myeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT liudi myeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT hanke myeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT liujing myeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT wangxiaowen myeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT yangwenting myeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT dongqingyang myeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT yangsongtao myeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT xiaxianzhu myeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT tangli myeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein
AT hefuchu myeloidlsectinisadap12coupledreceptorthatiscrucialforinflammatoryresponseinducedbyebolavirusglycoprotein