Department of Perioperative Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD, USA.
Sickle Cell Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Biochem Biophys Res Commun. 2021 May 28;555:196-201. doi: 10.1016/j.bbrc.2021.03.115. Epub 2021 Apr 5.
The nucleotide-binding domain leucine-rich repeat containing protein 3 (NLRP3) inflammasome is a critical inflammatory mechanism identified in platelets, which controls platelet activation and aggregation. We have recently shown that the platelet NLRP3 inflammasome is upregulated in sickle cell disease (SCD), which is mediated by Bruton tyrosine kinase (BTK). Here, we investigated the effect of pharmacological inhibition of NLRP3 and BTK on platelet aggregation and the formation of in vitro thrombi in Townes SCD mice. Mice were injected for 4 weeks with the NLRP3 inhibitor MCC950, the BTK inhibitor ibrutinib or vehicle control. NLRP3 activity, as monitored by caspase-1 activation, was upregulated in platelets from SCD mice, which was dependent on BTK. Large areas of platelet aggregates detected in the liver of SCD mice were decreased when mice were treated with MCC950 or ibrutinib. Moreover, platelet aggregation and in vitro thrombus formation were upregulated in SCD mice and were inhibited when mice were subjected to pharmacological inhibition of NLRP3 and BTK. Targeting the NLRP3 inflammasome might be a novel approach for antiplatelet therapy in SCD.
核苷酸结合域富含亮氨酸重复蛋白 3（NLRP3）炎症小体是在血小板中发现的一种关键炎症机制，它控制着血小板的激活和聚集。我们最近发现，镰状细胞病（SCD）中血小板 NLRP3 炎症小体上调，这是由 Bruton 酪氨酸激酶（BTK）介导的。在这里，我们研究了 NLRP3 和 BTK 的药理学抑制对 Townes SCD 小鼠血小板聚集和体外血栓形成的影响。小鼠连续 4 周注射 NLRP3 抑制剂 MCC950、BTK 抑制剂 ibrutinib 或载体对照。SCD 小鼠血小板中 caspase-1 激活监测到的 NLRP3 活性上调，这依赖于 BTK。当用 MCC950 或 ibrutinib 治疗时，SCD 小鼠肝脏中检测到的大块血小板聚集减少。此外，SCD 小鼠的血小板聚集和体外血栓形成增加，当对 NLRP3 和 BTK 进行药理学抑制时，这种增加被抑制。靶向 NLRP3 炎症小体可能是 SCD 抗血小板治疗的一种新方法。
