Interleukin-1β Mediates Arterial Thrombus Formation via NET-Associated Tissue Factor

Luca Liberale, Erik W Holy, Alexander Akhmedov, Nicole R Bonetti, Fabian Nietlispach, Christian M Matter, François Mach, Fabrizio Montecucco, Jürg H Beer, Francesco Paneni, Frank Ruschitzka, Peter Libby, Thomas F Lüscher, Giovanni G Camici

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Abstract

CANTOS reported reduced secondary atherothrombotic events in patients with residual inflammatory risk treated with the inhibitory anti-IL-1β antibody, Canakinumab. Yet, mechanisms that underlie this benefit remain elusive. Recent work has implicated formation of neutrophil extracellular traps (NETosis) in arterial thrombosis. Hence, the present study explored the potential link between IL-1β, NETs, and tissue factor (TF)-the key trigger of the coagulation cascade-in atherothrombosis. To this end, ST-elevation myocardial infarction (STEMI) patients from the Swiss multicenter trial SPUM-ACS were retrospectively and randomly selected based on their CRP levels. In particular, 33 patients with STEMI and high C-reactive protein (CRP) levels (≥ 10 mg/L) and, 33 with STEMI and low CRP levels (≤ 4 mg/L) were investigated. High CRP patients displayed elevated circulating IL-1β, NETosis, and NET-associated TF plasma levels compared with low CRP ones. Additionally, analysis of patients stratified by circulating IL-1β levels yielded similar results. Moreover, NETosis and NET-associated TF plasma levels correlated positively in the whole population. In addition to the above, translational research experiments provided mechanistic confirmation for the clinical data identifying IL-1β as the initial trigger for the release of the pro-coagulant, NET-associated TF. In conclusion, blunted TF presentation by activated neutrophils undergoing NETosis may provide a mechanistic explanation to reduced secondary atherothrombotic events as observed in canakinumab-treated patients in CANTOS.

Original languageEnglish
JournalJournal of Clinical Medicine
Volume8
Issue number12
DOIs
Publication statusPublished - Nov 26 2019

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Liberale, L., Holy, E. W., Akhmedov, A., Bonetti, N. R., Nietlispach, F., Matter, C. M., Mach, F., Montecucco, F., Beer, J. H., Paneni, F., Ruschitzka, F., Libby, P., Lüscher, T. F., & Camici, G. G. (2019). Interleukin-1β Mediates Arterial Thrombus Formation via NET-Associated Tissue Factor. Journal of Clinical Medicine, 8(12). https://doi.org/10.3390/jcm8122072