Defective NET clearance contributes to sustained FXII activation in COVID-19-associated pulmonary thrombo-inflammation
Englert, Hanna; Rangaswamy, Chandini; Deppermann, Carsten; Sperhake, Jan-Peter; Krisp, Christoph; Schreier, Danny; Gordon, Emma; Konrath, Sandra; Haddad, Munif; Pula, Giordano; Mailer, Reiner K; Schlüter, Hartmut; Kluge, Stefan; Langer, Florian; Püschel, Klaus; Panousis, Kosta; Stavrou, Evi X; Maas, Coen; Renné, Thomas; Frye, Maike
(2021) EBioMedicine, volume 67, pp. 1 - 9
(Article)
Abstract
BACKGROUND: Coagulopathy 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. METHODS: We performed proteomic analysis and immunostaining
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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. FINDINGS: FXII 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. 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. FUNDING: This 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).
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Keywords: Autopsy, COVID-19/metabolism, Case-Control Studies, Deoxyribonucleases/blood, Extracellular Traps/metabolism, Factor XII/metabolism, Humans, Lung/metabolism, Neutrophil Activation, Pneumonia, Proteomics, Pulmonary thrombo-inflammation, Thrombosis, COVID-19, NETs, FXII, General Biochemistry,Genetics and Molecular Biology, Journal Article
ISSN: 2352-3964
Publisher: Elsevier BV
Note: Funding Information: This study was supported by the European Union's Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie Grant Agreement No. 840189 , the Werner Otto Medical Foundation Hamburg (8/95) and German Research Foundation (DFG) grant FR 4239/1-1 (to M.F.) and grants A11/SFB877 , B08/SFB841 and P06/KFO306 of the DFG (to T.R.). We thank the Institute of Transfusion Medicine and the Microscopy Imaging Facility at the University Medical Center Hamburg, Germany, for obtaining healthy control plasma samples and for technical microscopy support, respectively. Funding Information: This study was supported by the European Union's Horizon 2020 Research and Innovation Programme under the Marie Sk?odowska-Curie Grant Agreement No. 840189, the Werner Otto Medical Foundation Hamburg (8/95) and German Research Foundation (DFG) grant FR 4239/1-1 (to M.F.) and grants A11/SFB877, B08/SFB841 and P06/KFO306 of the DFG (to T.R.). We thank the Institute of Transfusion Medicine and the Microscopy Imaging Facility at the University Medical Center Hamburg, Germany, for obtaining healthy control plasma samples and for technical microscopy support, respectively. Publisher Copyright: © 2021 The Authors
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