OC 55.2 - Dimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon

Tuesday, June 27, 2023

11:00 – 11:15 ET

Room: 510

Session Available As: On-Demand

Presenting Author(s)

Tristram A.J Ryan, BSc PhD (he/him/his)

Postdoctoral researcher
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Dublin, Dublin, Ireland

Co-Author(s)

AH

Alexander Hooftman

Postdoctoral researcher
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Dublin, Dublin, Ireland
AR

Aisling M. M. Rehill

Postdoctoral researcher
Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons, Dublin 2, Ireland
Dublin, Dublin, Ireland
MJ

Matt D. Johansen

Postdoctoral researcher
Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, Sydney, NSW, Australia
Sydney, New South Wales, Australia
EO

Eóin C. O'Brien

Postdoctoral researcher
Host Pathogen Interactions Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Dublin, Dublin, Ireland
JT

Juliana E. Toller-Kawahisa

Postdoctoral researcher
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Dublin, Dublin, Ireland
ED

Emily A. Day

Postdoctoral researcher
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Dublin, Dublin, Ireland
HW

Hauke J. Weiss

Final-year PhD candidate
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Dublin, Dublin, Ireland
CP

Christian G. Peace

3rd Year PhD candidate
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Dublin, Dublin, Ireland
AZ

Alessia Zotta

Final-Year PhD candidate
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Dublin, Dublin, Ireland
NH

Nicole G. Hansbro

Postdoctoral researcher
Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, Sydney, NSW, Australia
Sydney, New South Wales, Australia
JO

James S. O'Donnell, MB, PhD

Professor of Haematology
Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland,Dublin, Ireland
Dublin, Dublin, Ireland
PH

Philip M. Hansbro

Principal Investigator, Director of the Centenary UTS Centre for Inflammation
Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, Sydney, NSW, Australia
Sydney, New South Wales, Australia
RM

Rachel M. McLoughlin

Principal Investigator, Professor in Immunology, Biochemistry
Host Pathogen Interactions Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Dublin, Dublin, Ireland
MW

Małgorzata Wygrecka

Principal Investigator, Assistant Professor, Department of Medical Biochemistry
Center for Infection and Genomics of the Lung, Faculty of Medicine, Justus Liebig University, Giessen, Germany
Giessen, Hessen, Germany
Roger J.S. Preston, PhD

Principal Investigator, Lecturer in Vascular Biology
Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons, Dublin 2, Ireland
Dublin, Dublin, Ireland
ZZ

Zbigniew Zasłona

Postdoctoral researcher
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Dublin, Dublin, Ireland
LO

Luke A.J. O'Neill, FRS

Professor (Chair of Biochemistry)
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Dublin, Dublin, Ireland

Background: Excessive inflammation-associated coagulation can lead to life-threatening coagulopathies which can occur in sepsis and COVID-19. Dysregulated type I interferon signalling and the caspase-11 inflammasome are critical for macrophage tissue factor (TF) release and TF-dependent thrombin generation, highlighting this process as a potential therapeutic target for TF-mediated coagulopathy.

Aims: To investigate if the anti-inflammatory agent dimethyl fumarate (DMF), which is clinically approved for the treatment of psoriasis and multiple sclerosis, and the related experimental therapeutic agent 4-octyl itaconate (4-OI), modulate aberrant TF-mediated coagulation via inhibition of type I interferon in macrophages.

Methods: Mouse bone marrow-derived macrophages (BMDMs) and human PBMCs were treated with DMF or 4-OI and challenged with LPS before assessment of gene and protein expression by RT-PCR and western blotting. TF-dependent thrombin generation was analyzed via thrombin generation assay. In vivo, mice were treated with DMF or 4-OI and then challenged with LPS, E.coli, S.aureus, and SARS-CoV-2. Thrombin generation was assessed in plasma and lungs were examined for histological changes consistent with coagulopathy.

Results: We found that F3 is a type I interferon-stimulated gene and identify the type I interferon-TF axis as a critical inducer of bacterial and viral coagulation. DMF and 4-OI blocked LPS-induced F3 mRNA and TF protein expression in BMDMs in vitro via inhibition of Ifnb1. Additionally, they block type I interferon- and caspase-11-mediated pyroptosis, and subsequent TF release from BMDMs and TF-dependent thrombin generation. In vivo, DMF and 4-OI inhibit TF-dependent thrombin generation, lung thromboinflammation, and lethality induced by LPS, E.coli, and S.aureus, with 4-OI additionally attenuating inflammation-associated coagulation following SARS-CoV-2 infection.

Conclusion(s): Our results identify DMF and 4-OI as anticoagulants that inhibit TF-mediated coagulopathy via inhibition of the macrophage type I interferon-TF axis. This translational study supports clinical assessment of DMF and 4-OI for the treatment of infectious diseases where both inflammation and coagulation are key pathologic features.

Learning Objectives:

Upon completion, participants will be able to describe the key players in a novel signalling axis in macrophages that is important for thrombin generation.
Upon completion, participants will be able to identify the critical binding sites in the promoter of the human F3 gene that make it an interferon-stimulated gene.
Upon completion, participants will be able to name two pharmacological compounds that inhibit interferon-mediated thrombin generation.