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Dimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon.
Ryan, Tristram A J; Hooftman, Alexander; Rehill, Aisling M; Johansen, Matt D; Brien, Eóin C O'; Toller-Kawahisa, Juliana E; Wilk, Mieszko M; 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, Malgorzata; Preston, Roger J S; Zaslona, Zbigniew; O'Neill, Luke A J.
Afiliación
  • Ryan TAJ; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
  • Hooftman A; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
  • Rehill AM; Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin 2, Ireland.
  • Johansen MD; Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, Sydney, NSW, Australia.
  • Brien ECO; Host Pathogen Interactions Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
  • Toller-Kawahisa JE; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
  • Wilk MM; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
  • Day EA; Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
  • Weiss HJ; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
  • Sarvari P; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
  • Vozza EG; Center for Infection and Genomics of the Lung, German Center for Lung Research (DZL), Faculty of Medicine, Justus Liebig University, Giessen, Germany.
  • Schramm F; Host Pathogen Interactions Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
  • Peace CG; Center for Infection and Genomics of the Lung, German Center for Lung Research (DZL), Faculty of Medicine, Justus Liebig University, Giessen, Germany.
  • Zotta A; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
  • Miemczyk S; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
  • Nalkurthi C; Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, Sydney, NSW, Australia.
  • Hansbro NG; Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, Sydney, NSW, Australia.
  • McManus G; Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, Sydney, NSW, Australia.
  • O'Doherty L; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
  • Gargan S; Department of Infectious Diseases, St. James's Hospital, Dublin, Ireland.
  • Long A; Clinical Research Facility, St. James's Hospital, Dublin, Ireland.
  • Dunne J; Department of Clinical Medicine, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
  • Cheallaigh CN; Department of Clinical Medicine, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
  • Conlon N; Department of Clinical Medicine, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
  • Carty M; Department of Immunology, St James's Hospital, Dublin, Ireland.
  • Fallon PG; Department of Infectious Diseases, St. James's Hospital, Dublin, Ireland.
  • Mills KHG; Department of Clinical Medicine, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
  • Creagh EM; Clinical Research Facility, St. James's Hospital, Dublin, Ireland.
  • Donnell JSO; Department of Clinical Medicine, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
  • Hertzog PJ; Department of Immunology, St James's Hospital, Dublin, Ireland.
  • Hansbro PM; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
  • McLoughlin RM; Department of Clinical Medicine, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
  • Wygrecka M; School of Medicine, Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland.
  • Preston RJS; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
  • Zaslona Z; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
  • O'Neill LAJ; Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin 2, Ireland.
Nat Commun ; 14(1): 3513, 2023 06 14.
Article en En | MEDLINE | ID: mdl-37316487
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trombosis / Interferón Tipo I / COVID-19 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2023 Tipo del documento: Article País de afiliación: Irlanda Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trombosis / Interferón Tipo I / COVID-19 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2023 Tipo del documento: Article País de afiliación: Irlanda Pais de publicación: Reino Unido