Identification of Anticoagulant Properties of Dimethyl Fumarate and 4-Octyl Itaconate via Suppression of the Macrophage Type I Interferon-Tissue Factor Axis
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Ryan, Tristram Alexander, Identification of Anticoagulant Properties of Dimethyl Fumarate and 4-Octyl Itaconate via Suppression of the Macrophage Type I Interferon-Tissue Factor Axis, Trinity College Dublin, School of Biochemistry & Immunology, Biochemistry, 2023Download Item:
Abstract:
The host response to infection is characterized by activation of the innate immune and blood coagulation systems, which collectively detect, neutralize, and prevent dissemination of the invading pathogen, maintaining homeostasis. This relationship between inflammation and coagulation is highly conserved across species. Emerging evidence continues to unravel the mechanisms that govern the interplay between them, in particular where excessive inflammation can lead to life-threatening coagulopathy in conditions such as sepsis, disseminated intravascular coagulation, and COVID-19. Recently, dysregulated type I interferon (IFN) signalling and inflammasome activation in macrophages have been implicated as critical mediators of blood coagulation. During infection or injury, activation of macrophages induces expression and procoagulant activity of tissue factor (TF), a key initiator of blood coagulation. Macrophages release TF into the bloodstream during caspase-11-mediated pyroptosis, a form of lytic proinflammatory cell death. Excessive macrophage TF release and procoagulant activity subsequently drive dysregulated thrombin generation which can result in pathological thrombus formation and blood vessel occlusion. Aberrant coagulation may also trigger further detrimental inflammation, termed thromboinflammation.
In this thesis, I have explored further the crosstalk between innate immune signalling pathways and coagulation, in particular the mechanisms leading to TF (gene name F3) induction and release from macrophages following activation with lipopolysaccharide (LPS). I have found that F3 is a type I IFN stimulated gene, and describe for the first time a procoagulant type I IFN-TF axis in macrophages. Induction of type I IFN by pathogenic stimuli leads to increased expression of both F3 and caspase-11 in macrophages, which triggers pyroptosis and an increase in TF-dependent thrombin generation. This process is inhibited by two anti-inflammatory compounds. I have found that dimethyl fumarate (DMF), a clinically approved anti-inflammatory drug for the treatment of psoriasis and multiple sclerosis, and 4-octyl itaconate (4-OI), a similarly acting anti-inflammatory drug-in-development, prevent coagulation. Mechanistically, DMF and 4-OI inhibit F3 induction following bacterial or viral infection via suppression of Ifnb1. DMF and 4-OI also block activity of NF-kB and MAPK, the transcriptional regulators of F3. As a result, TF-dependent thrombin generation induced by both LPS and pyroptosis is inhibited in vitro.
These findings extended into mouse models of inflammation-associated coagulation. I found that DMF and 4-OI inhibit TF-dependent thrombin generation in mice following LPS challenge, as well as infection with E. coli and S. aureus, demonstrating that both DMF and 4-OI are potent anticoagulants in vivo. Inhibition of the type I IFN-TF axis by DMF and 4-OI also blocked downstream pulmonary thromboinflammation. In addition to these protective effects in models of gram-negative and gram-positive bacterial infection, 4-OI suppressed inflammation and coagulation in a mouse model of SARS-CoV-2 infection. Therefore, inhibition of the type I IFN-TF axis is an effective anticoagulant approach in vivo. Although current anticoagulants are effective in the clinic, they are associated with a significant risk of increased bleeding, particularly in sepsis patients. Therefore safer anticoagulants are urgently needed. Ideally, a new generation of anticoagulant therapies would reduce this bleeding risk, in addition to suppressing the concurrent inflammation associated with ? and that may also lead to ? coagulation. The data in this thesis elucidate a novel mechanism of F3 induction in macrophages, and provide the basis for the testing of anti-inflammatory therapies such as DMF and 4-OI-based compounds in clinical conditions of excessive inflammation-associated coagulation.
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Author: Ryan, Tristram Alexander
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Oneill, LukePublisher:
Trinity College Dublin. School of Biochemistry & Immunology. Discipline of BiochemistryType of material:
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