Defective NET clearance contributes to sustained FXII activation in COVID-19-associated pulmonary thrombo-inflammation.
COVID-19
FXII
NETs
Pulmonary thrombo-inflammation
Thrombosis
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
May 2021
May 2021
Historique:
received:
25
01
2021
revised:
19
04
2021
accepted:
21
04
2021
pubmed:
18
5
2021
medline:
9
6
2021
entrez:
17
5
2021
Statut:
ppublish
Résumé
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. We 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. 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. 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. 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).
Sections du résumé
BACKGROUND
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
METHODS
We 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.
FINDINGS
RESULTS
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
CONCLUSIONS
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
BACKGROUND
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).
Identifiants
pubmed: 34000623
pii: S2352-3964(21)00175-4
doi: 10.1016/j.ebiom.2021.103382
pmc: PMC8120108
pii:
doi:
Substances chimiques
Factor XII
9001-30-3
Deoxyribonucleases
EC 3.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
103382Subventions
Organisme : BLRD VA
ID : I01 BX003851
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL137695
Pays : United States
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest H.E. has a patent WO 2019/036719A2, licensed to Neutrolis Therapeutics, outside the submitted work. C.R. has a patent EP3570667A1, licensed to Neutrolis Therapeutics, outside the submitted work. K.Pa. is an employee and shareholder of CSL Limited and has patents 9.856.326, 9.856.325 and 9.518.127 issued, outside the submitted work. C.M. is part-time employee of TargED Biopharmaceuticals and has a patent WO2019185723A1 pending, both outside the submitted work. T.R. and the University of Hamburg have a patent (EU and U.S. reference numbers EP18736859.2 and US16/622064) licensed, outside of the submitted work. C.D., JP.S., C.K., D.S., E.G., S.Ko., M.H., G.P., R.M., H.S., K.Pü., E.S., and M.F. have nothing to disclose.