Blunted sFasL signalling exacerbates TNF‐driven neutrophil necroptosis in critically ill COVID‐19 patients. Issue 12 (11th December 2021)

• Record Type: Journal Article
• Authors: Schweizer, Tiziano A; Mairpady Shambat, Srikanth; Vulin, Clement; Hoeller, Sylvia; Acevedo, Claudio; Huemer, Markus; Gomez‐Mejia, Alejandro; Chang, Chun‐Chi; Baum, Jeruscha; Hertegonne, Sanne; Hitz, Eva; Scheier, Thomas C; Hofmaenner, Daniel A; Buehler, Philipp K; Moch, Holger; Schuepbach, Reto A; Brugger, Silvio D; Zinkernagel, Annelies S
• Is Part Of: Clinical & translational immunology. Volume 10:Issue 12(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12-11
• Subjects: COVID‐19 -- Fas (CD95) -- necroptosis -- neutrophils -- RIPK1 -- TNF‐α; Immunologic diseases -- Periodicals; Immunology -- Periodicals; Clinical medicine -- Periodicals; Immune System Diseases -- therapy; Immunotherapy; Immunologic Factors -- therapeutic use; Translational Medical Research; Molecular Targeted Therapy; Clinical medicine; Immunologic diseases; Immunology; Periodicals; Periodicals; Fulltext; Internet Resources; Periodicals; 616.079
• DOI: 10.1002/cti2.1357
• Languages: English
• ISSNs: 2050-0068

Abstract

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. Abstract : This work highlights the role of cell death ambiguity in neutrophils and its contribution to pathophysiology during critical COVID‐19. The inflammatory COVID‐19 environment provoked a TNF‐α‐induced necroptosis‐sensitive neutrophil subpopulation, characterised by elevated release of DAMPs, increased RIPK1 levels and a pivotal role for MLKL. Neutrophil necroptosis through the RIPK1‐RIPK3‐MLKL axis was further confirmed in COVID‐19 thrombus and lung biopsies. Blunted Fas engagement by sFasL was identified to drive elevated RIPK1 levels upon TNF‐α‐induced necroptosis, while decreased sFasL plasma levels in critically ill COVID‐19 patients correlated to elevated disease severity, which was masked by glucocorticoid treatment.