Blunted sFasL signalling exacerbates TNF‐driven neutrophil necroptosis in critically ill COVID‐19 patients
Abstract Objectives Critically ill coronavirus disease 2019 (COVID‐19) patients are characterised by a severely dysregulated cytokine profile and elevated neutrophil counts, impacting disease severity. However, it remains unclear how neutrophils contribute to pathophysiology during COVID‐19. Here, w...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-01-01
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| Series: | Clinical & Translational Immunology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cti2.1357 |
| _version_ | 1819095930954055680 |
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| author | Tiziano A Schweizer Srikanth Mairpady Shambat Clement Vulin Sylvia Hoeller Claudio Acevedo Markus Huemer Alejandro Gomez‐Mejia Chun‐Chi Chang Jeruscha Baum Sanne Hertegonne Eva Hitz Thomas C Scheier Daniel A Hofmaenner Philipp K Buehler Holger Moch Reto A Schuepbach Silvio D Brugger Annelies S Zinkernagel |
| author_facet | Tiziano A Schweizer Srikanth Mairpady Shambat Clement Vulin Sylvia Hoeller Claudio Acevedo Markus Huemer Alejandro Gomez‐Mejia Chun‐Chi Chang Jeruscha Baum Sanne Hertegonne Eva Hitz Thomas C Scheier Daniel A Hofmaenner Philipp K Buehler Holger Moch Reto A Schuepbach Silvio D Brugger Annelies S Zinkernagel |
| author_sort | Tiziano A Schweizer |
| collection | DOAJ |
| description | Abstract Objectives Critically ill coronavirus disease 2019 (COVID‐19) patients are characterised by a severely dysregulated cytokine profile and elevated neutrophil counts, impacting disease severity. However, it remains unclear how neutrophils contribute to pathophysiology during COVID‐19. Here, we assessed the impact of the dysregulated cytokine profile on the regulated cell death (RCD) programme of neutrophils. Methods Regulated cell death phenotype of neutrophils isolated from critically ill COVID‐19 patients or healthy donors and stimulated with COVID‐19 or healthy plasma ex vivo was assessed by flow cytometry, time‐lapse microscopy and cytokine multiplex analysis. Immunohistochemistry of COVID‐19 patients and control biopsies were performed to assess the in situ neutrophil RCD phenotype. Plasma cytokine levels of COVID‐19 patients and healthy donors were measured by multiplex analysis. Clinical parameters were correlated to cytokine levels of COVID‐19 patients. Results COVID‐19 plasma induced a necroptosis‐sensitive neutrophil phenotype, characterised by cell lysis, elevated release of damage‐associated molecular patterns (DAMPs), increased receptor‐interacting serine/threonine‐protein kinase (RIPK) 1 levels and mixed lineage kinase domain‐like pseudokinase (MLKL) involvement. The occurrence of neutrophil necroptosis MLKL axis was further confirmed in COVID‐19 thrombus and lung biopsies. Necroptosis was induced by the tumor necrosis factor receptor 1 (TNFRI)/TNF‐α axis. Moreover, reduction of soluble Fas ligand (sFasL) levels in COVID‐19 patients and hence decreased signalling to Fas directly increased RIPK1 levels, exacerbated TNF‐driven necroptosis and correlated with disease severity, which was abolished in patients treated with glucocorticoids. Conclusion Our results suggest a novel role for sFasL signalling in the TNF‐α‐induced RCD programme in neutrophils during COVID‐19 and a potential therapeutic target to curb inflammation and thus influence disease severity and outcome. |
| first_indexed | 2024-12-21T23:51:08Z |
| format | Article |
| id | doaj.art-7fd263ea29c7436da33567c8fe95612a |
| institution | Directory Open Access Journal |
| issn | 2050-0068 |
| language | English |
| last_indexed | 2024-12-21T23:51:08Z |
| publishDate | 2021-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical & Translational Immunology |
| spelling | doaj.art-7fd263ea29c7436da33567c8fe95612a2022-12-21T18:45:55ZengWileyClinical & Translational Immunology2050-00682021-01-011012n/an/a10.1002/cti2.1357Blunted sFasL signalling exacerbates TNF‐driven neutrophil necroptosis in critically ill COVID‐19 patientsTiziano A Schweizer0Srikanth Mairpady Shambat1Clement Vulin2Sylvia Hoeller3Claudio Acevedo4Markus Huemer5Alejandro Gomez‐Mejia6Chun‐Chi Chang7Jeruscha Baum8Sanne Hertegonne9Eva Hitz10Thomas C Scheier11Daniel A Hofmaenner12Philipp K Buehler13Holger Moch14Reto A Schuepbach15Silvio D Brugger16Annelies S Zinkernagel17Department of Infectious Diseases and Hospital Epidemiology University Hospital of Zurich University of Zurich Zurich SwitzerlandDepartment of Infectious Diseases and Hospital Epidemiology University Hospital of Zurich University of Zurich Zurich SwitzerlandDepartment of Infectious Diseases and Hospital Epidemiology University Hospital of Zurich University of Zurich Zurich SwitzerlandDepartment of Pathology and Molecular Pathology University Hospital of Zurich University of Zurich Zurich SwitzerlandDepartment of Infectious Diseases and Hospital Epidemiology University Hospital of Zurich University of Zurich Zurich SwitzerlandDepartment of Infectious Diseases and Hospital Epidemiology University Hospital of Zurich University of Zurich Zurich SwitzerlandDepartment of Infectious Diseases and Hospital Epidemiology University Hospital of Zurich University of Zurich Zurich SwitzerlandDepartment of Infectious Diseases and Hospital Epidemiology University Hospital of Zurich University of Zurich Zurich SwitzerlandDepartment of Infectious Diseases and Hospital Epidemiology University Hospital of Zurich University of Zurich Zurich SwitzerlandDepartment of Infectious Diseases and Hospital Epidemiology University Hospital of Zurich University of Zurich Zurich SwitzerlandDepartment of Infectious Diseases and Hospital Epidemiology University Hospital of Zurich University of Zurich Zurich SwitzerlandDepartment of Infectious Diseases and Hospital Epidemiology University Hospital of Zurich University of Zurich Zurich SwitzerlandInstitute for Intensive Care Medicine University Hospital of Zurich University of Zurich Zurich SwitzerlandInstitute for Intensive Care Medicine University Hospital of Zurich University of Zurich Zurich SwitzerlandDepartment of Pathology and Molecular Pathology University Hospital of Zurich University of Zurich Zurich SwitzerlandInstitute for Intensive Care Medicine University Hospital of Zurich University of Zurich Zurich SwitzerlandDepartment of Infectious Diseases and Hospital Epidemiology University Hospital of Zurich University of Zurich Zurich SwitzerlandDepartment of Infectious Diseases and Hospital Epidemiology University Hospital of Zurich University of Zurich Zurich SwitzerlandAbstract Objectives Critically ill coronavirus disease 2019 (COVID‐19) patients are characterised by a severely dysregulated cytokine profile and elevated neutrophil counts, impacting disease severity. However, it remains unclear how neutrophils contribute to pathophysiology during COVID‐19. Here, we assessed the impact of the dysregulated cytokine profile on the regulated cell death (RCD) programme of neutrophils. Methods Regulated cell death phenotype of neutrophils isolated from critically ill COVID‐19 patients or healthy donors and stimulated with COVID‐19 or healthy plasma ex vivo was assessed by flow cytometry, time‐lapse microscopy and cytokine multiplex analysis. Immunohistochemistry of COVID‐19 patients and control biopsies were performed to assess the in situ neutrophil RCD phenotype. Plasma cytokine levels of COVID‐19 patients and healthy donors were measured by multiplex analysis. Clinical parameters were correlated to cytokine levels of COVID‐19 patients. Results COVID‐19 plasma induced a necroptosis‐sensitive neutrophil phenotype, characterised by cell lysis, elevated release of damage‐associated molecular patterns (DAMPs), increased receptor‐interacting serine/threonine‐protein kinase (RIPK) 1 levels and mixed lineage kinase domain‐like pseudokinase (MLKL) involvement. The occurrence of neutrophil necroptosis MLKL axis was further confirmed in COVID‐19 thrombus and lung biopsies. Necroptosis was induced by the tumor necrosis factor receptor 1 (TNFRI)/TNF‐α axis. Moreover, reduction of soluble Fas ligand (sFasL) levels in COVID‐19 patients and hence decreased signalling to Fas directly increased RIPK1 levels, exacerbated TNF‐driven necroptosis and correlated with disease severity, which was abolished in patients treated with glucocorticoids. Conclusion Our results suggest a novel role for sFasL signalling in the TNF‐α‐induced RCD programme in neutrophils during COVID‐19 and a potential therapeutic target to curb inflammation and thus influence disease severity and outcome.https://doi.org/10.1002/cti2.1357COVID‐19Fas (CD95)necroptosisneutrophilsRIPK1TNF‐α |
| spellingShingle | Tiziano A Schweizer Srikanth Mairpady Shambat Clement Vulin Sylvia Hoeller Claudio Acevedo Markus Huemer Alejandro Gomez‐Mejia Chun‐Chi Chang Jeruscha Baum Sanne Hertegonne Eva Hitz Thomas C Scheier Daniel A Hofmaenner Philipp K Buehler Holger Moch Reto A Schuepbach Silvio D Brugger Annelies S Zinkernagel Blunted sFasL signalling exacerbates TNF‐driven neutrophil necroptosis in critically ill COVID‐19 patients Clinical & Translational Immunology COVID‐19 Fas (CD95) necroptosis neutrophils RIPK1 TNF‐α |
| title | Blunted sFasL signalling exacerbates TNF‐driven neutrophil necroptosis in critically ill COVID‐19 patients |
| title_full | Blunted sFasL signalling exacerbates TNF‐driven neutrophil necroptosis in critically ill COVID‐19 patients |
| title_fullStr | Blunted sFasL signalling exacerbates TNF‐driven neutrophil necroptosis in critically ill COVID‐19 patients |
| title_full_unstemmed | Blunted sFasL signalling exacerbates TNF‐driven neutrophil necroptosis in critically ill COVID‐19 patients |
| title_short | Blunted sFasL signalling exacerbates TNF‐driven neutrophil necroptosis in critically ill COVID‐19 patients |
| title_sort | blunted sfasl signalling exacerbates tnf driven neutrophil necroptosis in critically ill covid 19 patients |
| topic | COVID‐19 Fas (CD95) necroptosis neutrophils RIPK1 TNF‐α |
| url | https://doi.org/10.1002/cti2.1357 |
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