title: Caspase-1-mediated pathway promotes generation of thromboinflammatory microparticles.
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.forename: Andrea S
authors.initials: AS
authors.lastname: Rothmeier
authors.forename: Patrizia
authors.initials: P
authors.lastname: Marchese
authors.forename: Brian G
authors.initials: BG
authors.lastname: Petrich
authors.forename: Christian
authors.initials: C
authors.lastname: Furlan-Freguia
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ginsberg
authors.forename: Zaverio M
authors.initials: ZM
authors.lastname: Ruggeri
authors.forename: Wolfram
authors.initials: W
authors.lastname: Ruf
mesh_terms: D000199:Actins / Q000502:physiology; D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D020170:Caspase 1 / Q000502:physiology*; D055252:Cell-Derived Microparticles / Q000502:physiology*; D045604:Extracellular Fluid; D007113:Immunity, Innate; D058847:Inflammasomes / Q000502:physiology; D007249:Inflammation / Q000503:physiopathology; D008264:Macrophages / Q000502:physiology*; D021962:Membrane Microdomains / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011554:Pseudopodia / Q000502:physiology; D058486:Receptors, Purinergic P2X7 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013880:Thioredoxin-Disulfide Reductase / Q000502:physiology; D013879:Thioredoxins / Q000502:physiology; D013927:Thrombosis / Q000503:physiopathology
chemical_list: D000199:Actins; D058847:Inflammasomes; D058486:Receptors, Purinergic P2X7; D013879:Thioredoxins; D000255:Adenosine Triphosphate; D013880:Thioredoxin-Disulfide Reductase; D020170:Caspase 1