Interleukin-6 stimulates platelet 12-lipoxygenase to drive coagulation in inflammatory arthritis.

Costa, Daniela O. ORCID: https://orcid.org/0000-0001-8821-5898, Hughes, Stuart T. O., Jenkins, Robert H. ORCID: https://orcid.org/0000-0001-8500-9044, Cardus Figueras, Ana, Protty, Majd B., Tyrell, Victoria J., Hajeyah, Ali A., Burston, James J., Morgan, Bethan, Monaco, Federica, Morrin, Aisling S., Guy, Carol, Jenkins, P. Vince, Collins, Peter W. ORCID: https://orcid.org/0000-0002-6410-1324, Choy, Ernest ORCID: https://orcid.org/0000-0003-4459-8609, Jones, Simon A. ORCID: https://orcid.org/0000-0001-7297-9711 and O'Donnell, Valerie B. ORCID: https://orcid.org/0000-0003-4089-8460 2026. Interleukin-6 stimulates platelet 12-lipoxygenase to drive coagulation in inflammatory arthritis. Journal of Lipid Research 67 (8) , 101093. 10.1016/j.jlr.2026.101093

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Abstract

Rheumatoid arthritis (RA) is associated with significantly higher thrombotic risk, which is not mechanistically understood. In particular, the detailed mechanisms driving coagulation in arthritis have not been explored, despite the significant impact on patient morbidity and mortality. The role of platelet and blood cell enzymatically-oxidized phospholipids in driving thrombosis, and their regulation by inflammation, was tested using a mouse model (antigen-induced arthritis, AIA) and a human RA cohort. AIA induction significantly elevated plasma thrombin-antithrombin (TAT) complexes, sP-selectin and serum amyloid A (SAA), indicating inflammation and elevated coagulation. Concurrently, platelet-derived eoxPL and their IgG autoantibodies were elevated in whole blood and plasma. These indices were all suppressed by genetic deletion of IL-6Ra, while platelet Alox12 deletion prevented TAT, sP-selectin and eoxPL/autoantibody increases. Leukocyte Alox15 deletion did not impact circulating TATs or eoxPL. This indicates that IL-6 drives coagulation in AIA via upregulation of platelet Alox12. Conversely, synovial tissue demonstrated raised eoxPL exclusively from Alox15. In human RA, immunoreactivity towards platelet-derived eoxPL was elevated in early disease. Thus, while both LOX isoforms differentially contribute to AIA in mice, only Alox12 promotes thrombosis risk, while evidence for increased eoxPL exposure in early human RA was revealed. In summary, the IL-6/Alox12 axis drives platelet activation in AIA, providing a potential mechanistic explanation for recent clinical trial data proposing that anti-iL-6 therapy is associated with reduced coagulation in early RA. The pro-coagulant lipid membrane is proposed as a therapeutic target for preventing vascular events in autoimmune disease.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	Elsevier BV
ISSN:	0022-2275
Date of First Compliant Deposit:	6 July 2026
Date of Acceptance:	26 June 2026
Last Modified:	04 Aug 2026 11:15
URI:	https://orca.cardiff.ac.uk/id/eprint/187937

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