title: Dendritic cell PAR1-S1P3 signalling couples coagulation and inflammation.
abstract: Defining critical points of modulation across heterogeneous clinical syndromes may provide insight into new therapeutic approaches. Coagulation initiated by the cytokine-receptor family member known as tissue factor is a hallmark of systemic inflammatory response syndromes in bacterial sepsis and viral haemorrhagic fevers, and anticoagulants can be effective in severe sepsis with disseminated intravascular coagulation. The precise mechanism coupling coagulation and inflammation remains unresolved. Here we show that protease-activated receptor 1 (PAR1) signalling sustains a lethal inflammatory response that can be interrupted by inhibition of either thrombin or PAR1 signalling. The sphingosine 1-phosphate (S1P) axis is a downstream component of PAR1 signalling, and by combining chemical and genetic probes for S1P receptor 3 (S1P3) we show a critical role for dendritic cell PAR1-S1P3 cross-talk in regulating amplification of inflammation in sepsis syndrome. Conversely, dendritic cells sustain escalated systemic coagulation and are the primary hub at which coagulation and inflammation intersect within the lymphatic compartment. Loss of dendritic cell PAR1-S1P3 signalling sequesters dendritic cells and inflammation into draining lymph nodes, and attenuates dissemination of interleukin-1beta to the lungs. Thus, activation of dendritic cells by coagulation in the lymphatics emerges as a previously unknown mechanism that promotes systemic inflammation and lethality in decompensated innate immune responses.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Niessen
authors.forename: Florence
authors.initials: F
authors.lastname: Schaffner
authors.forename: Christian
authors.initials: C
authors.lastname: Furlan-Freguia
authors.forename: Rafal
authors.initials: R
authors.lastname: Pawlinski
authors.forename: Gourab
authors.initials: G
authors.lastname: Bhattacharjee
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.forename: Claudia K
authors.initials: CK
authors.lastname: Derian
authors.forename: Patricia
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.forename: Wolfram
authors.initials: W
authors.lastname: Ruf
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000502:physiology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D008208:Lymphatic System / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000502:physiology; D044463:Receptor, PAR-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors; D000099157:Sphingosine Kinase
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); D044463:Receptor, PAR-1; D049349:Receptors, Lysosphingolipid; D010975:Platelet Aggregation Inhibitors; D000099157:Sphingosine Kinase