Inhibiting the P2Y 12 Receptor in Megakaryocytes and Platelets Suppresses Interferon-Associated Responses.

The authors investigated the impact of antiplatelet therapy on the megakaryocyte (MK) and platelet transcriptome. RNA-sequencing was performed on MKs treated with aspirin or P2Y ₁₂ inhibitor, platelets from healthy volunteers receiving aspirin or P2Y ₁₂ inhibition, and platelets from patients with systemic lupus erythematosus (SLE). P2Y ₁₂ inhibition reduced gene expression and inflammatory pathways in MKs and platelets. In SLE, the interferon (IFN) pathway was elevated. In vitro experiments demonstrated the role of P2Y ₁₂ inhibition in reducing IFNα-induced platelet-leukocyte interactions and IFN signaling pathways. These results suggest that P2Y ₁₂ inhibition may have therapeutic potential for proinflammatory and autoimmune conditions like SLE.
Competing Interests: This work was supported by National Institutes of Health grants R01HL139909 (to Drs Berger and Buyon), R35HL144993 (to Dr Berger), 1OT2HL156812-01 (to Dr Berger), R01HL167917 (to Dr Barrett), and R01HL118049 (to Dr Voora). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.PerspectivesCOMPETENCY IN MEDICAL KNOWLEDGE: The comprehensive analysis of MK and platelet transcriptomes suppressed by P2Y12 inhibitors and their role in modulating immune reactions adds insights into understanding immune-mediated disorders and their therapeutic potential. P2Y12 inhibitors might synergize with existing treatments to provide more comprehensive control over immune dysregulation and thrombotic tendencies. TRANSLATIONAL OUTLOOK: Further investigation into the precise molecular mechanisms linking P2Y12 inhibition, platelet function, and immune modulation would provide a deeper understanding of the nonhemostatic effects of platelet directed therapies. This knowledge could uncover novel drug targets within platelet-mediated pathways. In addition to SLE, the role of platelet activation and its modulation by P2Y12 inhibitors could be investigated in other inflammatory conditions, expanding the potential applications of these agents.
(© 2024 Published by Elsevier on behalf of the American College of Cardiology Foundation.)