Abstract
Neutrophils through the release of neutrophil extracellular traps (NETs) containing active tissue factor (TF) are key components of thrombo-inflammation. Platelets-neutrophils interplay in ST elevation myocardial infarction (STEMI) promotes NET formation via inorganic polyphosphates (polyP) released by thrombin-activated platelets. NETs, however, are also induced by biomaterials in a platelet-independent manner. Considering the possible pleiotropic effects of Ticagrelor beyond platelet inhibition and the clinical need for novel antithrombotic strategies targeting inflammation, we investigated the effects of Ticagrelor on polyP and stent-induced NETs in STEMI. Neutrophils from healthy individuals and patients receiving Ticagrelor were stimulated with polyP or drug-eluting stents (DES) to produce NETs. To induce TF expression, neutrophils were further incubated with plasma obtained from the infarct-related artery (IRA) of STEMI patients. The effects of Ticagrelor on NETs and TF loading were assessed using fluorescence microscopy, flow cytometry, myeloperoxidase(MPO)/DNA complex ELISA, and a Western blot. Ticagrelor interrupts platelet–neutrophil interaction by attenuating NETs induced by polyP. However, Ticagrelor does not affect polyP secretion from thrombin-activated platelets. Similarly, the intracellular production of TF in neutrophils triggered by IRA plasma is not hindered by Ticagrelor. Furthermore, DES induce NETs and synchronous stimulation with IRA plasma leads to the formation of thrombogenic TF-bearing NETs. Ticagrelor inhibits stent-induced NET release. These findings suggest a novel immune-modulatory effect of Ticagrelor when it attenuates the formation of thrombogenic NETs.
Highlights
According to current knowledge, the interaction between platelets and neutrophils is crucially involved in the thrombotic process [1,2,3]
We found that, compared to Clopidogrel, Ticagrelor significantly attenuated the formation of polyP-induced neutrophil extracellular traps (NETs) from human neutrophils in vitro (Immunofluorescence, MPO/DNA complex ELISA) (Figure 1a–c)
The previously mentioned data suggest the particular activity of Ticagrelor to inhibit the formation of NETs by neutrophils triggered by polyP and coronary stents
Summary
The interaction between platelets and neutrophils is crucially involved in the thrombotic process [1,2,3]. We have previously demonstrated that, in ST elevation myocardial infarction (STEMI), the interaction between platelets and neutrophils is accomplished through the secretion of linear inorganic short-chain polyphosphate (polyP) from thrombin-activated platelets [4]. PolyP is released from platelets upon their activation and can elicit potent proinflammatory responses [5,6,7]. In the microenvironment of infarct-related artery (IRA), platelets are primed to release polyP triggering neutrophils to form thrombogenic/tissue factor (TF)-bearing neutrophil extracellular traps (NETs). Reducing the burden of cardiovascular diseases is a clinical need today and novel or alternative therapeutic strategies, which target thrombo-inflammation such as a polyP-neutrophil interaction or thrombogenic NETs, were missing until now
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