title: Endogenous EPCR/aPC-PAR1 signaling prevents inflammation-induced vascular leakage and lethality.
abstract: Protease activated receptor 1 (PAR1) signaling can play opposing roles in sepsis, either promoting dendritic cell (DC)-dependent coagulation and inflammation or reducing sepsis lethality due to activated protein C (aPC) therapy. To further define this PAR1 paradox, we focused on the vascular effects of PAR1 signaling. Pharmacological perturbations of the intravascular coagulant balance were combined with genetic mouse models to dissect the roles of endogenously generated thrombin and aPC during escalating systemic inflammation. Acute blockade of the aPC pathway with a potent inhibitory antibody revealed that thrombin-PAR1 signaling increases inflammation-induced vascular hyperpermeability. Conversely, aPC-PAR1 signaling and the endothelial cell PC receptor (EPCR) prevented vascular leakage, and pharmacologic or genetic blockade of this pathway sensitized mice to LPS-induced lethality. Signaling-selective aPC variants rescued mice with defective PC activation from vascular leakage and lethality. Defects in the aPC pathway were fully compensated by sphingosine 1 phosphate receptor 3 (S1P3) deficiency or by selective agonists of the S1P receptor 1 (S1P1), indicating that PAR1 signaling contributes to setting the tone for the vascular S1P1/S1P3 balance. Thus, the activating proteases and selectivity in coupling to S1P receptor subtypes determine vascular PAR1 signaling specificity in systemic inflammatory response syndromes in vivo.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Niessen
authors.forename: Christian
authors.initials: C
authors.lastname: Furlan-Freguia
authors.forename: José A
authors.initials: JA
authors.lastname: Fernández
authors.forename: Laurent O
authors.initials: LO
authors.lastname: Mosnier
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Castellino
authors.forename: Hartmut
authors.initials: H
authors.lastname: Weiler
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
authors.forename: Wolfram
authors.initials: W
authors.lastname: Ruf
mesh_terms: D000818:Animals; D019559:Capillary Leak Syndrome / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D002199:Capillary Permeability / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004211:Disseminated Intravascular Coagulation / Q000503:physiopathology*; D000074283:Endothelial Protein C Receptor; D004730:Endothelium, Vascular / Q000503:physiopathology; D004731:Endotoxins / Q000633:toxicity; D004789:Enzyme Activation; D006023:Glycoproteins / Q000502:physiology*; D006629:Hirudins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D011486:Protein C / Q000235:genetics / Q000502:physiology*; D044463:Receptor, PAR-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface; D049349:Receptors, Lysosphingolipid / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D000081025:Sphingosine-1-Phosphate Receptors; D018746:Systemic Inflammatory Response Syndrome / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D013876:Thiophenes / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000502:physiology; D013925:Thromboplastin / Q000502:physiology; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C517408:AUY 954; D000074283:Endothelial Protein C Receptor; D004731:Endotoxins; D006023:Glycoproteins; D006629:Hirudins; D009419:Nerve Tissue Proteins; C080248:Procr protein, mouse; D011486:Protein C; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface; D049349:Receptors, Lysosphingolipid; C501285:S1pr3 protein, mouse; C491561:Sip1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; D013876:Thiophenes; D015091:beta-Alanine; C044101:endotoxin, Escherichia coli; D013925:Thromboplastin; D013917:Thrombin