Inhibiting the P2Y12 Receptor in Megakaryocytes and Platelets Suppresses Interferon-Associated Responses

[Display omitted] •Platelets and MKs are implicated in inflammation and immunity, prompting the nonhemostatic investigation of platelet-directed therapies.•P2Y12 inhibitors, distinct from ASA, attenuate the IFNα response pathway in both MKs and platelets. Notably, the IFNα pathway is increased in platelets isolated from patients with SLE. P2Y12 inhibitors could hold therapeutic potential for inhibiting platelet-mediated inflammation in proinflammatory conditions like SLE.•Using MKs as an in vitro model to study platelet transcriptome dynamics offers a powerful approach to understand the complex biology of platelets.•Exploring the clinical applicability of P2Y12 inhibition in targeting inflammatory and autoimmune diseases and investigating combination therapies for enhanced efficacy provides new insights into reducing platelet-mediated thromboinflammation and improving patient outcomes. 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 P2Y12 inhibitor, platelets from healthy volunteers receiving aspirin or P2Y12 inhibition, and platelets from patients with systemic lupus erythematosus (SLE). P2Y12 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 P2Y12 inhibition in reducing IFNα-induced platelet-leukocyte interactions and IFN signaling pathways. These results suggest that P2Y12 inhibition may have therapeutic potential for proinflammatory and autoimmune conditions like SLE.