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Article: H7N9 influenza A virus activation of necroptosis in human monocytes links innate and adaptive immune responses
Title | H7N9 influenza A virus activation of necroptosis in human monocytes links innate and adaptive immune responses |
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Authors | |
Issue Date | 2019 |
Publisher | Nature Publishing Group: Open Access Journals - Option C. The Journal's web site is located at http://www.nature.com/cddis/index.html |
Citation | Cell Death & Disease, 2019, v. 10 n. 6, p. article no. 442 How to Cite? |
Abstract | We previously demonstrated that avian influenza A H7N9 virus preferentially infected CD14+ monocyte in human peripheral blood mononuclear cells (PBMCs), which led to apoptosis. To better understand H7N9 pathogenesis in relation to monocyte cell death, we showed here that extensive phosphorylation of mixed lineage kinase domain-like (MLKL) protein occurred concurrently with the activation of caspases-8, -9 and -3 in H7N9-infected monocytes at 6 h post infection (hpi), indicating that apoptosis and necroptosis pathways were simultaneously activated. The apoptotic morphology was readily observed in H7N9-infected monocytes with transmission electron microscopy (TEM), while the pan-caspase inhibitor, IDN6556 (IDN), accelerated cell death through necroptosis as evidenced by the increased level of pMLKL accompanied with cell swelling and plasma membrane rupture. Most importantly, H7N9-induced cell death could only be stopped by the combined treatment of IDN and necrosulfonamide (NSA), a pMLKL membrane translocation inhibitor, but not by individual inhibition of caspase or RIPK3. Our data further showed that activation of apoptosis and necroptosis pathways in monocytes differentially contributed to the immune response of monocytes upon H7N9 infection. Specifically, caspase inhibition significantly enhanced, while RIPK3 inhibition reduced the early expression of type I interferons and cytokine/chemokines in H7N9-infected monocytes. Moreover, culture supernatants from IDN-treated H7N9-infected monocyte promoted the expression of co-stimulatory molecule CD80, CD83 and CD86 on freshly isolated monocytes and monocyte-derived dendritic cells (MDCs) and enhanced the capacity of MDCs to induce CD3+ T-cell proliferation in vitro. In contrast, these immune stimulatory effects were abrogated by using culture supernatants from H7N9-infected monocyte with RIPK3 inhibition. In conclusion, our findings indicated that H7N9 infection activated both apoptosis and necroptosis in monocytes. An intact RIPK3 activity is required for upregulation of innate immune responses, while caspase activation suppresses the immune response. |
Persistent Identifier | http://hdl.handle.net/10722/273959 |
ISSN | 2023 Impact Factor: 8.1 2023 SCImago Journal Rankings: 2.447 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Lee, CY | - |
dc.contributor.author | Zhang, J | - |
dc.contributor.author | Chu, H | - |
dc.contributor.author | Li, C | - |
dc.contributor.author | Zhu, H | - |
dc.contributor.author | Mak, WWN | - |
dc.contributor.author | Chen, Y | - |
dc.contributor.author | Kok, KH | - |
dc.contributor.author | To, KKW | - |
dc.contributor.author | Yuen, KY | - |
dc.date.accessioned | 2019-08-18T14:52:10Z | - |
dc.date.available | 2019-08-18T14:52:10Z | - |
dc.date.issued | 2019 | - |
dc.identifier.citation | Cell Death & Disease, 2019, v. 10 n. 6, p. article no. 442 | - |
dc.identifier.issn | 2041-4889 | - |
dc.identifier.uri | http://hdl.handle.net/10722/273959 | - |
dc.description.abstract | We previously demonstrated that avian influenza A H7N9 virus preferentially infected CD14+ monocyte in human peripheral blood mononuclear cells (PBMCs), which led to apoptosis. To better understand H7N9 pathogenesis in relation to monocyte cell death, we showed here that extensive phosphorylation of mixed lineage kinase domain-like (MLKL) protein occurred concurrently with the activation of caspases-8, -9 and -3 in H7N9-infected monocytes at 6 h post infection (hpi), indicating that apoptosis and necroptosis pathways were simultaneously activated. The apoptotic morphology was readily observed in H7N9-infected monocytes with transmission electron microscopy (TEM), while the pan-caspase inhibitor, IDN6556 (IDN), accelerated cell death through necroptosis as evidenced by the increased level of pMLKL accompanied with cell swelling and plasma membrane rupture. Most importantly, H7N9-induced cell death could only be stopped by the combined treatment of IDN and necrosulfonamide (NSA), a pMLKL membrane translocation inhibitor, but not by individual inhibition of caspase or RIPK3. Our data further showed that activation of apoptosis and necroptosis pathways in monocytes differentially contributed to the immune response of monocytes upon H7N9 infection. Specifically, caspase inhibition significantly enhanced, while RIPK3 inhibition reduced the early expression of type I interferons and cytokine/chemokines in H7N9-infected monocytes. Moreover, culture supernatants from IDN-treated H7N9-infected monocyte promoted the expression of co-stimulatory molecule CD80, CD83 and CD86 on freshly isolated monocytes and monocyte-derived dendritic cells (MDCs) and enhanced the capacity of MDCs to induce CD3+ T-cell proliferation in vitro. In contrast, these immune stimulatory effects were abrogated by using culture supernatants from H7N9-infected monocyte with RIPK3 inhibition. In conclusion, our findings indicated that H7N9 infection activated both apoptosis and necroptosis in monocytes. An intact RIPK3 activity is required for upregulation of innate immune responses, while caspase activation suppresses the immune response. | - |
dc.language | eng | - |
dc.publisher | Nature Publishing Group: Open Access Journals - Option C. The Journal's web site is located at http://www.nature.com/cddis/index.html | - |
dc.relation.ispartof | Cell Death & Disease | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.title | H7N9 influenza A virus activation of necroptosis in human monocytes links innate and adaptive immune responses | - |
dc.type | Article | - |
dc.identifier.email | Lee, CY: cyalee@hku.hk | - |
dc.identifier.email | Zhang, J: zhangajx@hkucc.hku.hk | - |
dc.identifier.email | Chu, H: hinchu@hku.hk | - |
dc.identifier.email | Li, C: canlee@hku.hk | - |
dc.identifier.email | Chen, Y: yettacyx@hku.hk | - |
dc.identifier.email | Kok, KH: khkok@hku.hk | - |
dc.identifier.email | To, KKW: kelvinto@hku.hk | - |
dc.identifier.email | Yuen, KY: kyyuen@hkucc.hku.hk | - |
dc.identifier.authority | Zhang, J=rp00413 | - |
dc.identifier.authority | Chu, H=rp02125 | - |
dc.identifier.authority | Kok, KH=rp01455 | - |
dc.identifier.authority | To, KKW=rp01384 | - |
dc.identifier.authority | Yuen, KY=rp00366 | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.1038/s41419-019-1684-0 | - |
dc.identifier.pmid | 31165725 | - |
dc.identifier.scopus | eid_2-s2.0-85066935434 | - |
dc.identifier.hkuros | 301122 | - |
dc.identifier.volume | 10 | - |
dc.identifier.issue | 6 | - |
dc.identifier.spage | article no. 442 | - |
dc.identifier.epage | article no. 442 | - |
dc.identifier.isi | WOS:000470936500005 | - |
dc.publisher.place | United Kingdom | - |
dc.identifier.issnl | 2041-4889 | - |