Andrea S. Rothmeier

Bio: Andrea S. Rothmeier is an academic researcher from Scripps Research Institute. The author has contributed to research in topics: Tissue factor & Integrin. The author has an hindex of 9, co-authored 13 publications receiving 527 citations. Previous affiliations of Andrea S. Rothmeier include Ludwig Maximilian University of Munich.

Protease-activated receptor 2 signaling in inflammation

Abstract: Protease-activated receptors (PARs) are G protein-coupled receptors that are activated by proteolytical cleavage of the amino-terminus and thereby act as sensors for extracellular proteases. While coagulation proteases activate PARs to regulate hemostasis, thrombosis, and cardiovascular function, PAR2 is also activated in extravascular locations by a broad array of serine proteases, including trypsin, tissue kallikreins, coagulation factors VIIa and Xa, mast cell tryptase, and transmembrane serine proteases. Administration of PAR2-specific agonistic and antagonistic peptides, as well as studies in PAR2 knockout mice, identified critical functions of PAR2 in development, inflammation, immunity, and angiogenesis. Here, we review these roles of PAR2 with an emphasis on the role of coagulation and other extracellular protease pathways that cleave PAR2 in epithelial, immune, and neuronal cells to regulate physiological and pathophysiological processes.

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.

Tissue Factor: An Essential Mediator of Hemostasis and Trigger of Thrombosis.

Abstract: Tissue factor (TF) is the high-affinity receptor and cofactor for factor (F)VII/VIIa The TF-FVIIa complex is the primary initiator of blood coagulation and plays an essential role in hemostasis TF is expressed on perivascular cells and epithelial cells at organ and body surfaces where it forms a hemostatic barrier TF also provides additional hemostatic protection to vital organs, such as the brain, lung, and heart Under pathological conditions, TF can trigger both arterial and venous thrombosis For instance, atherosclerotic plaques contain high levels of TF on macrophage foam cells and microvesicles that drives thrombus formation after plaque rupture In sepsis, inducible TF expression on monocytes leads to disseminated intravascular coagulation In cancer patients, tumors release TF-positive microvesicles into the circulation that may contribute to venous thrombosis TF also has nonhemostatic roles For instance, TF-dependent activation of the coagulation cascade generates coagulation proteases, such as FVIIa, FXa, and thrombin, which induce signaling in a variety of cells by cleavage of protease-activated receptors This review will focus on the roles of TF in protective hemostasis and pathological thrombosis

Platelets as Cellular Effectors of Inflammation in Vascular Diseases

Abstract: Platelets are chief effector cells in hemostasis. In addition, they are multifaceted inflammatory cells with functions that span the continuum from innate immune responses to adaptive immunity. Activated platelets have key thromboinflammatory activities in a variety of vascular disorders and vasculopathies. Recently identified inflammatory and immune activities provide insights into the biology of these versatile blood cells that are directly relevant to human vascular diseases.