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Caspase-1–mediated pathway promotes generation of thromboinflammatory microparticles
Andrea S. Rothmeier, … , Zaverio M. Ruggeri, Wolfram Ruf
Andrea S. Rothmeier, … , Zaverio M. Ruggeri, Wolfram Ruf
Published February 23, 2015
Citation Information: J Clin Invest. 2015;125(4):1471-1484. https://doi.org/10.1172/JCI79329.
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Research Article Hematology Article has an altmetric score of 1

Caspase-1–mediated pathway promotes generation of thromboinflammatory microparticles

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Abstract

Extracellular ATP is a signal of tissue damage and induces macrophage responses that amplify inflammation and coagulation. Here we demonstrate that ATP signaling through macrophage P2X7 receptors uncouples the thioredoxin (TRX)/TRX reductase (TRXR) system and activates the inflammasome through endosome-generated ROS. TRXR and inflammasome activity promoted filopodia formation, cellular release of reduced TRX, and generation of extracellular thiol pathway–dependent, procoagulant microparticles (MPs). Additionally, inflammasome-induced activation of an intracellular caspase-1/calpain cysteine protease cascade degraded filamin, thereby severing bonds between the cytoskeleton and tissue factor (TF), the cell surface receptor responsible for coagulation activation. This cascade enabled TF trafficking from rafts to filopodia and ultimately onto phosphatidylserine-positive, highly procoagulant MPs. Furthermore, caspase-1 specifically facilitated cell surface actin exposure, which was required for the final release of highly procoagulant MPs from filopodia. Together, the results of this study delineate a thromboinflammatory pathway and suggest that components of this pathway have potential as pharmacological targets to simultaneously attenuate inflammation and innate immune cell–induced thrombosis.

Authors

Andrea S. Rothmeier, Patrizia Marchese, Brian G. Petrich, Christian Furlan-Freguia, Mark H. Ginsberg, Zaverio M. Ruggeri, Wolfram Ruf

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Figure 4

TF and integrin β1 incorporation into MPs requires functional lipid raft domains.

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TF and integrin β1 incorporation into MPs requires functional lipid raft...
(A) Effect of filipin treatment on TF cell surface and MP activity with control and ATP-stimulated TFKI macrophages; mean ± SD, n = 7, *P < 0.05, ANOVA (Bonferroni). (B) Effect of filipin on MP incorporation of PSGL1, TF, integrin β1, PDI, and γ-actin detected by Western blotting. (C) Effect of filipin treatment on the release of TRX and γ-actin into the MP-depleted supernatants detected by Western blotting. (D) FACS analysis of MPs released from ATP-stimulated TFKI macrophages with or without filipin pretreatment. Event counts are displayed in the indicated gates of large and small MPs. Right panel: Scatter plot of TF and PS staining for MPs from ATP-stimulated cells with (gray) or without (green) filipin pretreatment. (E) Effects of filipin on filopodia formation and localization of TF (red) in control and ATP-activated macrophages. Cells were counterstained after permeabilization for F-actin (green) and nuclei (blue); scale bar: 10 μm. Right panel: Quantification of TF distribution on filopodia versus the cell body; mean ± SD, n = 6, ***P < 0.001, t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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