| Autor: |
Ryan, Tristram A. J., Hooftman, Alexander, Rehill, Aisling M., Johansen, Matt D., Brien, Eóin C. O’, Toller-Kawahisa, Juliana E., Wilk, Mieszko, Day, Emily A., Weiss, Hauke J., Sarvari, Pourya, Vozza, Emilio G., Schramm, Fabian, Peace, Christian G., Zotta, Alessia, Miemczyk, Stefan, Nalkurthi, Christina, Hansbro, Nicole G., McManus, Gavin, O’Doherty, Laura, Gargan, Siobhan, Long, Aideen, Dunne, Jean, Cheallaigh, Clíona Ní, Conlon, Niall, Carty, Michael, Fallon, Padraic G., Mills, Kingston H. G., Creagh, Emma M., Donnell, James S. O’, Hertzog, Paul J., Hansbro, Philip M., McLoughlin, Rachel M., Wygrecka, Małgorzata, Preston, Roger J. S., Zasłona, Zbigniew, Neill, Luke A. J. O’ |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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