Dimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
14 06 2023
14 06 2023
Historique:
received:
25
01
2023
accepted:
01
06
2023
medline:
16
6
2023
pubmed:
15
6
2023
entrez:
14
6
2023
Statut:
epublish
Résumé
Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to disseminated intravascular coagulation, one of the leading causes of mortality worldwide. Recently, type I interferon (IFN) signaling has been shown to be required for tissue factor (TF; gene name F3) release from macrophages, a critical initiator of coagulation, providing an important mechanistic link between innate immunity and coagulation. The mechanism of release involves type I IFN-induced caspase-11 which promotes macrophage pyroptosis. Here we find that F3 is a type I IFN-stimulated gene. Furthermore, F3 induction by lipopolysaccharide (LPS) is inhibited by the anti-inflammatory agents dimethyl fumarate (DMF) and 4-octyl itaconate (4-OI). Mechanistically, inhibition of F3 by DMF and 4-OI involves suppression of Ifnb1 expression. Additionally, they block type I IFN- and caspase-11-mediated macrophage pyroptosis, and subsequent TF release. Thereby, DMF and 4-OI inhibit TF-dependent thrombin generation. In vivo, DMF and 4-OI suppress TF-dependent thrombin generation, pulmonary thromboinflammation, and lethality induced by LPS, E. coli, and S. aureus, with 4-OI additionally attenuating inflammation-associated coagulation in a model of SARS-CoV-2 infection. Our results identify the clinically approved drug DMF and the pre-clinical tool compound 4-OI as anticoagulants that inhibit TF-mediated coagulopathy via inhibition of the macrophage type I IFN-TF axis.
Identifiants
pubmed: 37316487
doi: 10.1038/s41467-023-39174-1
pii: 10.1038/s41467-023-39174-1
pmc: PMC10265568
doi:
Substances chimiques
Anticoagulants
0
4-octyl itaconate
0
Thromboplastin
9035-58-9
Dimethyl Fumarate
FO2303MNI2
Lipopolysaccharides
0
Thrombin
EC 3.4.21.5
Caspases
EC 3.4.22.-
Interferon Type I
0
Banques de données
Dryad
['10.5061/dryad.6wwpzgn28']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3513Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 202846/Z/16/Z
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2023. The Author(s).
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