The NLRP3 inflammasome and bruton's tyrosine kinase in platelets co-regulate platelet activation, aggregation, and in vitro thrombus formation

Pranav Murthy, Filip Durco, Jennifer L. Miller-Ocuin, Teiko Takedai, Shruthi Shankar, Xiaoyan Liang, Xiao Liu, Xiangdong Cui, Ulka Sachdev, Dominik Rath, Michael T. Lotze, Herbert J. Zeh, Meinrad Gawaz, Alexander N. Weber, Sebastian Vogel

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Cleavage of interleukin-1β (IL-1β) is a key inflammatory event in immune cells and platelets, which is mediated by nucleotide-binding domain leucine rich repeat containing protein (NLRP3)-dependent activation of caspase-1. In immune cells, NLRP3 and caspase-1 form inflammasome complexes with the adaptor proteins apoptosis-associated speck-like protein containing a CARD (ASC) and bruton's tyrosine kinase (BTK). In platelets, however, the regulatory triggers and the functional effects of the NLRP3 inflammasome are unknown. Here, we show in vitro that the platelet NLRP3 inflammasome contributes to platelet activation, aggregation, and thrombus formation. NLRP3 activity, as monitored by caspase-1 activation and cleavage and secretion of IL-1β, was upregulated in activated platelets, which was dependent on platelet BTK. Pharmacological inhibition or genetic ablation of BTK in platelets led to decreased platelet activation, aggregation, and in vitro thrombus formation. We identify a functionally relevant link between BTK and NLRP3 in platelets, with potential implications in disease states associated with abnormal coagulation and inflammation.

Original languageEnglish (US)
Pages (from-to)230-236
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume483
Issue number1
DOIs
StatePublished - Jan 29 2017
Externally publishedYes

Keywords

  • Aggregation
  • Bruton's tyrosine kinase
  • NLRP3
  • Platelets
  • Thrombosis

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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