tetano
Editor, Senior Moderator
EBioMedicine
. 2021 May 14;67:103382.
doi: 10.1016/j.ebiom.2021.103382. Online ahead of print.
Defective NET clearance contributes to sustained FXII activation in COVID-19-associated pulmonary thrombo-inflammation
Hanna Englert[SUP] 1 [/SUP], Chandini Rangaswamy[SUP] 1 [/SUP], Carsten Deppermann[SUP] 1 [/SUP], Jan-Peter Sperhake[SUP] 2 [/SUP], Christoph Krisp[SUP] 1 [/SUP], Danny Schreier[SUP] 1 [/SUP], Emma Gordon[SUP] 3 [/SUP], Sandra Konrath[SUP] 1 [/SUP], Munif Haddad[SUP] 1 [/SUP], Giordano Pula[SUP] 1 [/SUP], Reiner K Mailer[SUP] 1 [/SUP], Hartmut Schl?ter[SUP] 1 [/SUP], Stefan Kluge[SUP] 4 [/SUP], Florian Langer[SUP] 5 [/SUP], Klaus P?schel[SUP] 2 [/SUP], Kosta Panousis[SUP] 6 [/SUP], Evi X Stavrou[SUP] 7 [/SUP], Coen Maas[SUP] 8 [/SUP], Thomas Renn?[SUP] 1 [/SUP], Maike Frye[SUP] 9 [/SUP]
Affiliations
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 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 acafajf?eFXII 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).
Keywords: COVID-19; FXII; NETs; Pulmonary thrombo-inflammation; Thrombosis.
. 2021 May 14;67:103382.
doi: 10.1016/j.ebiom.2021.103382. Online ahead of print.
Defective NET clearance contributes to sustained FXII activation in COVID-19-associated pulmonary thrombo-inflammation
Hanna Englert[SUP] 1 [/SUP], Chandini Rangaswamy[SUP] 1 [/SUP], Carsten Deppermann[SUP] 1 [/SUP], Jan-Peter Sperhake[SUP] 2 [/SUP], Christoph Krisp[SUP] 1 [/SUP], Danny Schreier[SUP] 1 [/SUP], Emma Gordon[SUP] 3 [/SUP], Sandra Konrath[SUP] 1 [/SUP], Munif Haddad[SUP] 1 [/SUP], Giordano Pula[SUP] 1 [/SUP], Reiner K Mailer[SUP] 1 [/SUP], Hartmut Schl?ter[SUP] 1 [/SUP], Stefan Kluge[SUP] 4 [/SUP], Florian Langer[SUP] 5 [/SUP], Klaus P?schel[SUP] 2 [/SUP], Kosta Panousis[SUP] 6 [/SUP], Evi X Stavrou[SUP] 7 [/SUP], Coen Maas[SUP] 8 [/SUP], Thomas Renn?[SUP] 1 [/SUP], Maike Frye[SUP] 9 [/SUP]
Affiliations
- PMID: 34000623
- DOI: 10.1016/j.ebiom.2021.103382
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 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 acafajf?eFXII 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).
Keywords: COVID-19; FXII; NETs; Pulmonary thrombo-inflammation; Thrombosis.