tetano
Editor, Senior Moderator
Clin Transl Immunology
. 2021 Dec 11;10(12):e1357.
doi: 10.1002/cti2.1357. eCollection 2021.
Blunted sFasL signalling exacerbates TNF-driven neutrophil necroptosis in critically ill COVID-19 patients
Tiziano A Schweizer[SUP] 1 [/SUP], Srikanth Mairpady Shambat[SUP] 1 [/SUP], Clement Vulin[SUP] 1 [/SUP], Sylvia Hoeller[SUP] 2 [/SUP], Claudio Acevedo[SUP] 1 [/SUP], Markus Huemer[SUP] 1 [/SUP], Alejandro Gomez-Mejia[SUP] 1 [/SUP], Chun-Chi Chang[SUP] 1 [/SUP], Jeruscha Baum[SUP] 1 [/SUP], Sanne Hertegonne[SUP] 1 [/SUP], Eva Hitz[SUP] 1 [/SUP], Thomas C Scheier[SUP] 1 [/SUP], Daniel A Hofmaenner[SUP] 3 [/SUP], Philipp K Buehler[SUP] 3 [/SUP], Holger Moch[SUP] 2 [/SUP], Reto A Schuepbach[SUP] 3 [/SUP], Silvio D Brugger[SUP] 1 [/SUP], Annelies S Zinkernagel[SUP] 1 [/SUP]
Affiliations
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.
Keywords: COVID‐19; Fas (CD95); RIPK1; TNF‐α; necroptosis; neutrophils.
. 2021 Dec 11;10(12):e1357.
doi: 10.1002/cti2.1357. eCollection 2021.
Blunted sFasL signalling exacerbates TNF-driven neutrophil necroptosis in critically ill COVID-19 patients
Tiziano A Schweizer[SUP] 1 [/SUP], Srikanth Mairpady Shambat[SUP] 1 [/SUP], Clement Vulin[SUP] 1 [/SUP], Sylvia Hoeller[SUP] 2 [/SUP], Claudio Acevedo[SUP] 1 [/SUP], Markus Huemer[SUP] 1 [/SUP], Alejandro Gomez-Mejia[SUP] 1 [/SUP], Chun-Chi Chang[SUP] 1 [/SUP], Jeruscha Baum[SUP] 1 [/SUP], Sanne Hertegonne[SUP] 1 [/SUP], Eva Hitz[SUP] 1 [/SUP], Thomas C Scheier[SUP] 1 [/SUP], Daniel A Hofmaenner[SUP] 3 [/SUP], Philipp K Buehler[SUP] 3 [/SUP], Holger Moch[SUP] 2 [/SUP], Reto A Schuepbach[SUP] 3 [/SUP], Silvio D Brugger[SUP] 1 [/SUP], Annelies S Zinkernagel[SUP] 1 [/SUP]
Affiliations
- PMID: 34938538
- PMCID: PMC8665925
- DOI: 10.1002/cti2.1357
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.
Keywords: COVID‐19; Fas (CD95); RIPK1; TNF‐α; necroptosis; neutrophils.