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

Ryan, TAJ; Hooftman, A; Rehill, AM; Johansen, MD; Brien, ECO; Toller-Kawahisa, JE; Wilk, MM; Day, EA; Weiss, HJ; Sarvari, P; Vozza, EG; Schramm, F; Peace, CG; Zotta, A; Miemczyk, S; Nalkurthi, C; Hansbro, NG; McManus, G; O'Doherty, L; Gargan, S; Long, A; Dunne, J; Cheallaigh, CN; Conlon, N; Carty, M; Fallon, PG; Mills, KHG; Creagh, EM; Donnell, JSO; Hertzog, PJ; Hansbro, PM; McLoughlin, RM; Wygrecka, M; Preston, RJS; Zasłona, Z; O'Neill, LAJ

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

Ryan, TAJ Hooftman, A Rehill, AM Johansen, MD Brien, ECO Toller-Kawahisa, JE Wilk, MM Day, EA Weiss, HJ Sarvari, P Vozza, EG Schramm, F Peace, CG Zotta, A Miemczyk, S Nalkurthi, C Hansbro, NG McManus, G O'Doherty, L Gargan, S Long, A Dunne, J Cheallaigh, CN Conlon, N Carty, M Fallon, PG Mills, KHG Creagh, EM Donnell, JSO Hertzog, PJ Hansbro, PM McLoughlin, RM Wygrecka, M Preston, RJS Zasłona, Z O'Neill, LAJ

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Publisher:: Springer Nature
Publication Type:: Journal Article
Citation:: Nat Commun, 2023, 14, (1), pp. 3513
Issue Date:: 2023-06-14

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Field	Value	Language
dc.contributor.author	Ryan, TAJ
dc.contributor.author	Hooftman, A
dc.contributor.author	Rehill, AM
dc.contributor.author	Johansen, MD
dc.contributor.author	Brien, ECO
dc.contributor.author	Toller-Kawahisa, JE
dc.contributor.author	Wilk, MM
dc.contributor.author	Day, EA
dc.contributor.author	Weiss, HJ
dc.contributor.author	Sarvari, P
dc.contributor.author	Vozza, EG
dc.contributor.author	Schramm, F
dc.contributor.author	Peace, CG
dc.contributor.author	Zotta, A
dc.contributor.author	Miemczyk, S
dc.contributor.author	Nalkurthi, C
dc.contributor.author	Hansbro, NG
dc.contributor.author	McManus, G
dc.contributor.author	O'Doherty, L
dc.contributor.author	Gargan, S
dc.contributor.author	Long, A
dc.contributor.author	Dunne, J
dc.contributor.author	Cheallaigh, CN
dc.contributor.author	Conlon, N
dc.contributor.author	Carty, M
dc.contributor.author	Fallon, PG
dc.contributor.author	Mills, KHG
dc.contributor.author	Creagh, EM
dc.contributor.author	Donnell, JSO
dc.contributor.author	Hertzog, PJ
dc.contributor.author	Hansbro, PM
dc.contributor.author	McLoughlin, RM
dc.contributor.author	Wygrecka, M
dc.contributor.author	Preston, RJS
dc.contributor.author	Zasłona, Z
dc.contributor.author	O'Neill, LAJ
dc.date.accessioned	2023-08-09T05:27:43Z
dc.date.available	2023-06-01
dc.date.available	2023-08-09T05:27:43Z
dc.date.issued	2023-06-14
dc.identifier.citation	Nat Commun, 2023, 14, (1), pp. 3513
dc.identifier.issn	2041-1723
dc.identifier.issn	2041-1723
dc.identifier.uri	http://hdl.handle.net/10453/171764
dc.description.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.
dc.format	Electronic
dc.language	eng
dc.publisher	Springer Nature
dc.relation.ispartof	Nat Commun
dc.relation.isbasedon	10.1038/s41467-023-39174-1
dc.rights	info:eu-repo/semantics/restrictedAccess
dc.subject.mesh	Humans
dc.subject.mesh	Anticoagulants
dc.subject.mesh	Thromboplastin
dc.subject.mesh	Dimethyl Fumarate
dc.subject.mesh	Escherichia coli
dc.subject.mesh	Inflammation
dc.subject.mesh	Lipopolysaccharides
dc.subject.mesh	Staphylococcus aureus
dc.subject.mesh	Thrombin
dc.subject.mesh	COVID-19
dc.subject.mesh	SARS-CoV-2
dc.subject.mesh	Thrombosis
dc.subject.mesh	Macrophages
dc.subject.mesh	Caspases
dc.subject.mesh	Interferon Type I
dc.subject.mesh	Macrophages
dc.subject.mesh	Humans
dc.subject.mesh	Escherichia coli
dc.subject.mesh	Staphylococcus aureus
dc.subject.mesh	Thrombosis
dc.subject.mesh	Inflammation
dc.subject.mesh	Caspases
dc.subject.mesh	Thrombin
dc.subject.mesh	Lipopolysaccharides
dc.subject.mesh	Thromboplastin
dc.subject.mesh	Interferon Type I
dc.subject.mesh	Anticoagulants
dc.subject.mesh	Dimethyl Fumarate
dc.subject.mesh	COVID-19
dc.subject.mesh	SARS-CoV-2
dc.title	Dimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon.
dc.type	Journal Article
utslib.citation.volume	14
utslib.location.activity	England
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CFI - Centre for Inflammation
utslib.copyright.status	in_progress	*
dc.date.updated	2023-08-09T05:27:38Z
pubs.issue	1
pubs.publication-status	Published online
pubs.volume	14
utslib.citation.issue	1

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/171764