Cheah Lih T, Khalil Jawad S, McKay Mary, Ali Mohammad, Duval Cedric, Unsworth Amanda J, Naseem Khalid M
Discovery and Translational Science Department, Leeds Institute of Cardiovascular & Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK.
Cells. 2025 Jun 16;14(12):906. doi: 10.3390/cells14120906.
Beyond haemostasis and thrombosis, platelets are increasingly recognized for playing a crucial role in modulating immunoinflammation. Toll-like receptors (TLRs) constitute the first line of defence against infection and injury, with their engagement stimulating thrombotic and immune responses in platelets. Hence, anti-platelet drugs have been used to treat patients with infections and inflammation. However, due to the increased risk of bleeding with current anti-platelet drugs, alternative therapeutic targets need to be identified to ameliorate the consequences of inflammation-driven platelet hyperactivation. Previously, we demonstrated that resting platelets exhibit a metabolic plasticity that facilitates fuel selection flexibility, while in contrast, thrombin-stimulated platelets become highly glycolytic. Since multiple aspects of platelet activation require energy in terms of ATP, we investigated metabolic alterations in TLR1/TLR2-activated platelets. In this study, we have demonstrated that TLR1/TLR2-induced platelet activation reprogrammed platelets to upregulate glycolysis via CD36-linked mechanisms. In addition, we showed that this glycolytic flux is controlled by hexokinase (HK), which plays a crucial role in TLR1/TLR2-induced platelet aggregation. Targeting platelet metabolism plasticity may offer a novel strategy to inhibit platelet function in TLR-initiated diseases.
除了止血和血栓形成外，血小板在调节免疫炎症方面发挥的关键作用日益受到认可。Toll样受体（TLRs）构成了抵御感染和损伤的第一道防线，其激活会刺激血小板的血栓形成和免疫反应。因此，抗血小板药物已被用于治疗感染和炎症患者。然而，由于目前的抗血小板药物会增加出血风险，需要确定替代治疗靶点，以改善炎症驱动的血小板过度活化的后果。此前，我们证明静息血小板表现出代谢可塑性，有利于燃料选择的灵活性，而相比之下，凝血酶刺激的血小板则高度糖酵解。由于血小板激活的多个方面在ATP方面都需要能量，我们研究了TLR1/TLR2激活的血小板中的代谢变化。在本研究中，我们证明TLR1/TLR2诱导的血小板激活通过CD36相关机制使血小板重编程以上调糖酵解。此外，我们表明这种糖酵解通量受己糖激酶（HK）控制，HK在TLR1/TLR2诱导的血小板聚集中起关键作用。针对血小板代谢可塑性可能为抑制TLR引发疾病中的血小板功能提供一种新策略。
