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首页|Blunted Fas signaling favors RIPK1-driven neutrophil necroptosis in critically ill COVID-19 patients
10.1101/2021.03.19.436166
来源：bioRxiv_logobioRxiv

Blunted Fas signaling favors RIPK1-driven neutrophil necroptosis in critically ill COVID-19 patients

Blunted Fas signaling favors RIPK1-driven neutrophil necroptosis in critically ill COVID-19 patients

Hoeller Sylvia 1Acevedo Claudio 2Baum Jeruscha 2Hofmaenner Daniel A. 3Chang Chun-Chi 2Huemer Markus 2Gomez-Mejia Alejandro 2Shambat Srikanth Mairpady 2Schuepbach Reto A. 3Buehler Philipp K. 3Hitz Eva 2Vulin Cl¨|ment 2Brugger Silvio D. 2Moch Holger 1Zinkernagel Annelies S. 2Schweizer Tiziano A. 2Hertegonne Sanne2

1. Department of Pathology and Molecular Pathology, University Hospital of Zurich, University of Zurich 2. Department of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, University of Zurich 3. Institute for Intensive Care Medicine, University Hospital of Zurich, University of Zurich

基础医学临床医学细胞生物学

Hoeller Sylvia,Acevedo Claudio,Baum Jeruscha,Hofmaenner Daniel A.,Chang Chun-Chi,Huemer Markus,Gomez-Mejia Alejandro,Shambat Srikanth Mairpady,Schuepbach Reto A.,Buehler Philipp K.,Hitz Eva,Vulin Cl¨|ment,Brugger Silvio D.,Moch Holger,Zinkernagel Annelies S.,Schweizer Tiziano A.,Hertegonne Sanne.Blunted Fas signaling favors RIPK1-driven neutrophil necroptosis in critically ill COVID-19 patients[EB/OL].(2025-03-28)[2025-10-27].https://www.biorxiv.org/content/10.1101/2021.03.19.436166.点此复制

Abstract Critically ill COVID-19 patients are characterized by a severely dysregulated cytokine profile and elevated neutrophil counts, which are thought to contribute to disease severity. However, to date it remains unclear how neutrophils contribute to pathophysiology during COVID-19. Here, we assessed the impact of the dysregulated cytokine profile on the tightly regulated cell death program of neutrophils. We show that in a subpopulation of neutrophils, canonical apoptosis was skewed towards rapidly occurring necroptosis. This phenotype was characterized by abrogated caspase-8 activity and increased RIPK1 levels, favoring execution of necroptosis via the RIPK1-RIPK3-MLKL axis, as further confirmed in COVID-19 biopsies. Moreover, reduction of sFas-L levels in COVID-19 patients and hence decreased signaling to Fas directly increased RIPK1 levels and correlated with disease severity. Our results suggest an important role for Fas signaling in the regulation of cell death program ambiguity via the ripoptosome in neutrophils during COVID-19 and a potential therapeutic target to curb inflammation and thus influence disease severity and outcome.

COVID-19neutrophilscell deathFasRIPK1

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