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      NLRP3 inflammasome and bruton tyrosine kinase inhibition interferes with upregulated platelet aggregation and in vitro thrombus formation in sickle cell mice.

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          Abstract

          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.

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          Author and article information

          Journal
          Biochem Biophys Res Commun
          Biochemical and biophysical research communications
          Elsevier BV
          1090-2104
          0006-291X
          May 28 2021
          : 555
          Affiliations
          [1 ] Department of Perioperative Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD, USA.
          [2 ] Sickle Cell Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
          [3 ] Light Microscopy Core, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
          [4 ] 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. Electronic address: zquezado@cc.nih.gov.
          Article
          NIHMS1690922 S0006-291X(21)00513-1
          10.1016/j.bbrc.2021.03.115
          8085042
          33831782
          c02c2011-c9f0-48a9-b442-bf6078a3ecc7
          History

          Platelets,Platelet aggregation,NLRP3 inflammasome,Bruton tyrosin kinase,Sickle cell disease

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