Dimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon

Tristram A. J. Ryan, Alexander Hooftman, Aisling M. Rehill, Matt D. Johansen, Eóin C. O’ Brien, Juliana E. Toller-Kawahisa, Mieszko M. Wilk, Emily A. Day, Hauke J. Weiss, Pourya Sarvari, Emilio G. Vozza, Fabian Schramm, Christian G. Peace, Alessia Zotta, Stefan Miemczyk, Christina Nalkurthi, Nicole G. Hansbro, Gavin McManus, Laura O’Doherty, Siobhan Gargan, Aideen Long, Jean Dunne, Clíona Ní Cheallaigh, Niall Conlon, Michael Carty, Padraic G. Fallon, Kingston H. G. Mills, Emma M. Creagh, James S. O’ Donnell, Paul J. Hertzog, Philip M. Hansbro, Rachel M. McLoughlin, Małgorzata Wygrecka, Roger J. S. Preston, Zbigniew Zasłona and Luke A. J. O’Neill ()
Additional contact information
Tristram A. J. Ryan: Trinity Biomedical Sciences Institute, Trinity College Dublin
Alexander Hooftman: Trinity Biomedical Sciences Institute, Trinity College Dublin
Aisling M. Rehill: RCSI University of Medicine and Health Sciences
Matt D. Johansen: Centenary Institute and University of Technology Sydney, Faculty of Science
Eóin C. O’ Brien: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin
Juliana E. Toller-Kawahisa: Trinity Biomedical Sciences Institute, Trinity College Dublin
Mieszko M. Wilk: Trinity Biomedical Sciences Institute, Trinity College Dublin
Emily A. Day: Trinity Biomedical Sciences Institute, Trinity College Dublin
Hauke J. Weiss: Trinity Biomedical Sciences Institute, Trinity College Dublin
Pourya Sarvari: German Center for Lung Research (DZL), Faculty of Medicine, Justus Liebig University
Emilio G. Vozza: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin
Fabian Schramm: German Center for Lung Research (DZL), Faculty of Medicine, Justus Liebig University
Christian G. Peace: Trinity Biomedical Sciences Institute, Trinity College Dublin
Alessia Zotta: Trinity Biomedical Sciences Institute, Trinity College Dublin
Stefan Miemczyk: Centenary Institute and University of Technology Sydney, Faculty of Science
Christina Nalkurthi: Centenary Institute and University of Technology Sydney, Faculty of Science
Nicole G. Hansbro: Centenary Institute and University of Technology Sydney, Faculty of Science
Gavin McManus: Trinity Biomedical Sciences Institute, Trinity College Dublin
Laura O’Doherty: St. James’s Hospital
Siobhan Gargan: School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin
Aideen Long: School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin
Jean Dunne: St James’s Hospital
Clíona Ní Cheallaigh: St. James’s Hospital
Niall Conlon: St. James’s Hospital
Michael Carty: Trinity Biomedical Sciences Institute, Trinity College Dublin
Padraic G. Fallon: School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin
Kingston H. G. Mills: Trinity Biomedical Sciences Institute, Trinity College Dublin
Emma M. Creagh: Trinity Biomedical Sciences Institute, Trinity College Dublin
James S. O’ Donnell: RCSI University of Medicine and Health Sciences
Paul J. Hertzog: Hudson Institute of Medical Research
Philip M. Hansbro: Centenary Institute and University of Technology Sydney, Faculty of Science
Rachel M. McLoughlin: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin
Małgorzata Wygrecka: German Center for Lung Research (DZL), Faculty of Medicine, Justus Liebig University
Roger J. S. Preston: RCSI University of Medicine and Health Sciences
Zbigniew Zasłona: Trinity Biomedical Sciences Institute, Trinity College Dublin
Luke A. J. O’Neill: Trinity Biomedical Sciences Institute, Trinity College Dublin

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39174-1

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