PMID- 32455533 OWN - NLM STAT- MEDLINE DCOM- 20210216 LR - 20210216 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 21 IP - 10 DP - 2020 May 21 TI - Ticagrelor Exerts Immune-Modulatory Effect by Attenuating Neutrophil Extracellular Traps. LID - 10.3390/ijms21103625 [doi] LID - 3625 AB - 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. FAU - Mitsios, Alexandros AU - Mitsios A AD - Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece. FAU - Chrysanthopoulou, Akrivi AU - Chrysanthopoulou A AD - Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece. FAU - Arampatzioglou, Athanasios AU - Arampatzioglou A AD - Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece. FAU - Angelidou, Iliana AU - Angelidou I AD - Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece. FAU - Vidali, Veroniki AU - Vidali V AUID- ORCID: 0000-0001-9020-8726 AD - Natural Products Synthesis and Bioorganic Chemistry Laboratory, Institute of Nanoscience and Nanotechnology, NCSR "Demokritos", 15310 Athens, Greece. FAU - Ritis, Konstantinos AU - Ritis K AD - Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece. AD - First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece. FAU - Skendros, Panagiotis AU - Skendros P AD - Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece. AD - First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece. FAU - Stakos, Dimitrios AU - Stakos D AD - Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece. AD - Cardiology Department, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece. LA - eng PT - Journal Article DEP - 20200521 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Immunologic Factors) RN - 0 (Platelet Aggregation Inhibitors) RN - 0 (Polyphosphates) RN - 9007-49-2 (DNA) RN - EC 1.11.1.7 (Peroxidase) RN - EC 3.4.21.5 (Thrombin) RN - GLH0314RVC (Ticagrelor) SB - IM MH - Aged MH - Blood Platelets/drug effects/metabolism MH - Cells, Cultured MH - DNA/metabolism MH - Extracellular Traps/*drug effects/metabolism MH - Female MH - Humans MH - Immunologic Factors/*pharmacology/therapeutic use MH - Male MH - Middle Aged MH - Neutrophils/*drug effects/immunology MH - Peroxidase/metabolism MH - Platelet Aggregation Inhibitors/*pharmacology/therapeutic use MH - Polyphosphates/metabolism MH - Thrombin/metabolism MH - Ticagrelor/*pharmacology/therapeutic use PMC - PMC7279443 OTO - NOTNLM OT - inorganic polyphosphate OT - myocardial infraction OT - neutrophil OT - neutrophil extracellular traps OT - thrombo-inflammation OT - ticagrelor COIS- The authors declare that this study (Principal investigator D. Stakos) received funding from an Externally Sponsored Scientific Research grant from AstraZeneca (ESR#81835). The funder provided Ticagrelor (Research Use Only) and proposed the working concentration for in vitro experiments. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. All authors declare no conflict of interest. EDAT- 2020/05/28 06:00 MHDA- 2021/02/17 06:00 PMCR- 2020/05/01 CRDT- 2020/05/28 06:00 PHST- 2020/04/23 00:00 [received] PHST- 2020/05/14 00:00 [revised] PHST- 2020/05/19 00:00 [accepted] PHST- 2020/05/28 06:00 [entrez] PHST- 2020/05/28 06:00 [pubmed] PHST- 2021/02/17 06:00 [medline] PHST- 2020/05/01 00:00 [pmc-release] AID - ijms21103625 [pii] AID - ijms-21-03625 [pii] AID - 10.3390/ijms21103625 [doi] PST - epublish SO - Int J Mol Sci. 2020 May 21;21(10):3625. doi: 10.3390/ijms21103625.