Defective NET clearance contributes to sustained FXII activation in COVID-19-associated pulmonary thrombo-inflammation.

Hanna Englert,Christoph Krisp,Stefan Kluge,Coen Maas,Klaus Püschel,Danny Schreier,Giordano Pula,Kosta Panousis,Thomas Renné,Hartmut Schlüter,Reiner K Mailer,Munif Haddad,Carsten Deppermann,Maike Frye,Evi X Stavrou,Chandini Rangaswamy,Emma Gordon,Sandra Konrath,Florian Länger ,Jan‐Peter Sperhake

doi:10.1016/j.ebiom.2021.103382

Abstract

BackgroundCoagulopathy and inflammation are hallmarks of Coronavirus disease 2019 (COVID-19) and are associated with increased mortality. Clinical and experimental data have revealed a role for neutrophil extracellular traps (NETs) in COVID-19 disease. The mechanisms that drive thrombo-inflammation in COVID-19 are poorly understood.MethodsWe performed proteomic analysis and immunostaining of postmortem lung tissues from COVID-19 patients and patients with other lung pathologies. We further compared coagulation factor XII (FXII) and DNase activities in plasma samples from COVID-19 patients and healthy control donors and determined NET-induced FXII activation using a chromogenic substrate assay.FindingsFXII expression and activity were increased in the lung parenchyma, within the pulmonary vasculature and in fibrin-rich alveolar spaces of postmortem lung tissues from COVID-19 patients. In agreement with this, plasmaaac acafajföeFXII activation (FXIIa) was increased in samples from COVID-19 patients. Furthermore, FXIIa colocalized with NETs in COVID-19 lung tissue indicating that NETs accumulation leads to FXII contact activation in COVID-19. We further showed that an accumulation of NETs is partially due to impaired NET clearance by extracellular DNases as DNase substitution improved NET dissolution and reduced FXII activation in vitro.InterpretationCollectively, our study supports that the NET/FXII axis contributes to the pathogenic chain of procoagulant and proinflammatory responses in COVID-19. Targeting both NETs and FXIIa may offer a potential novel therapeutic strategy.FundingThis study was supported by the European Union (840189), the Werner Otto Medical Foundation Hamburg (8/95) and the German Research Foundation (FR4239/1-1, A11/SFB877, B08/SFB841 and P06/KFO306).

Highlights

Research in ContextEvidence before this studyDuring the outbreak of the Coronavirus disease 2019 (COVID19) pandemic, initial studies highlighted that Severe acute respiratory syndrome coronavirus type 2 infections are associated with a range of thrombotic complications and overactive immune cell reactions
We further found that neutrophil extracellular traps (NETs) degradation is impaired in COVID-19, suggesting that defective NET clearance can contribute to sustained factor XII (FXII) activation in COVID-19-associated pulmonary thromboinflammation
We show that NETs colocalize with the active serine protease FXIIa, in COVID-19 lung tissues indicating that NETs provide a platform for FXII contact activation in COVID-19

Summary

Introduction

Research in ContextEvidence before this studyDuring the outbreak of the Coronavirus disease 2019 (COVID19) pandemic, initial studies highlighted that Severe acute respiratory syndrome coronavirus type 2 infections are associated with a range of thrombotic complications and overactive immune cell reactions. Based on our previous work in the field of vascular biology, thrombosis and inflammation, we aimed to investigate the role of neutrophil extracellular traps (NETs) and the coagulation factor XII (FXII) in COVID-19. We showed that activated FXII (FXIIa) is increased in lung tissue and plasma from COVID-19 patients, indicating elevated intrinsic coagulation. FXIIa colocalized with NETs in COVID-19 lung tissues, suggesting NETs to provide a platform for FXII contact activation. Interpretation: Collectively, our study supports that the NET/FXII axis contributes to the pathogenic chain of procoagulant and proinflammatory responses in COVID-19. Targeting both NETs and FXIIa may offer a potential novel therapeutic strategy.

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