EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice.
Infection and inflammation are invariably associated with activation of the blood coagulation mechanism, secondary to the inflammation-induced expression of the coagulation initiator tissue factor (TF) on innate immune cells. By investigating the role of cell-surface receptors for coagulation factors in mouse endotoxemia, we found that the protein C receptor (ProcR; EPCR) was required for the normal in vivo and in vitro induction of lipopolysaccharide (LPS)-regulated gene expression. In cultured bone marrow-derived myeloid cells and in monocytic RAW264.7 cells, the LPS-induced expression of functionally active TF, assembly of the ternary TF-VIIa-Xa initiation complex of blood coagulation, and the EPCR-dependent activation of protease-activated receptor 2 (PAR2) by the ternary TF-VIIa-Xa complex were required for the normal LPS induction of messenger RNAs encoding the TLR3/4 signaling adaptor protein Pellino-1 and the transcription factor interferon regulatory factor 8. In response to in vivo challenge with LPS, mice lacking EPCR or PAR2 failed to fully initiate an interferon-regulated gene expression program that included the Irf8 target genes Lif, Iigp1, Gbp2, Gbp3, and Gbp6. The inflammation-induced expression of TF and crosstalk with EPCR, PAR2, and TLR4 therefore appear necessary for the normal evolution of interferon-regulated host responses.
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI;
Hai Po H
HP
Liang
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI;
Edward J
EJ
Kerschen
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI;
Irene
I
Hernandez
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI;
Sreemanti
S
Basu
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI;
Mark
M
Zogg
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI;
Fady
F
Botros
Department of Pediatrics, The Medical College of Wisconsin, The Children's Research Institute of Children's Hospital of Wisconsin, Milwaukee, WI;
Shuang
S
Jia
Department of Pediatrics, The Medical College of Wisconsin, The Children's Research Institute of Children's Hospital of Wisconsin, Milwaukee, WI;
Martin J
MJ
Hessner
Department of Molecular and Experimental Medicine, and.
John H
JH
Griffin
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA; and.
Wolfram
W
Ruf
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; Department of Physiology, The Medical College of Wisconsin, Milwaukee, WI.
Hartmut
H
Weiler
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics; D001779:Blood Coagulation Factors / Q000494:pharmacology*; D002478:Cells, Cultured; D000074283:Endothelial Protein C Receptor; D019446:Endotoxemia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D007372:Interferons / Q000378:metabolism*; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044464:Receptor, PAR-2 / Q000819:agonists* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000502:physiology*
D001779:Blood Coagulation Factors; D000074283:Endothelial Protein C Receptor; D008070:Lipopolysaccharides; C080248:Procr protein, mouse; D044464:Receptor, PAR-2; D011956:Receptors, Cell Surface; D007372:Interferons