Caspase-1-mediated pathway promotes generation of thromboinflammatory microparticles

• Authors: Andrea S. Rothmeier, Scripps Research Institute; Patrizia Marchese, Scripps Research Institute; Brian Petrich, Emory University; Christian Furlan-Freguia, Scripps Research Institute; Mark H. Ginsberg, University of California San Diego; Zaverio M. Ruggeri, Scripps Research Institute; Wolfram Ruf, Scripps Research Institute
• Journal Title: Journal of Clinical Investigation
• Volume: Volume 125, Number 4
• Publisher: American Society for Clinical Investigation | 2015-04-01, Pages 1471-1484
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1172/JCI79329
• Subjects: Health Sciences, Immunology; Health Sciences, General
• Keywords: Science & Technology; Life Sciences & Biomedicine; Medicine, Research & Experimental; Research & Experimental Medicine; PROTEIN-DISULFIDE-ISOMERASE; TISSUE FACTOR ACTIVITY; ENDOTHELIAL-CELLS; THIOREDOXIN REDUCTASE; REDOX REGULATION; P2X7 RECEPTOR; LIPID RAFTS; IN-VIVO; PHOSPHATIDYLSERINE EXPOSURE; RHEUMATOID-ARTHRITIS

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.