EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice.

Abstract

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.

• Authors: Hai Po H Liang, Edward J Kerschen, Irene Hernandez, Sreemanti Basu, Mark Zogg, Fady Botros, Shuang Jia, Martin J Hessner, John H Griffin, Wolfram Ruf, Hartmut Weiler
• Journal: Blood (Blood) Vol. 125 Issue 18 Pg. 2845-54 (Apr 30 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 25733582 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society of Hematology.

Chemical References

• Blood Coagulation Factors
• Endothelial Protein C Receptor
• Lipopolysaccharides
• Procr protein, mouse
• Receptor, PAR-2
• Receptors, Cell Surface
• Interferons

Topics

• Animals
• Blood Coagulation (drug effects, genetics)
• Blood Coagulation Factors (pharmacology)
• Cells, Cultured
• Endothelial Protein C Receptor
• Endotoxemia (chemically induced, genetics, metabolism)
• Gene Expression Regulation (drug effects)
• Interferons (metabolism)
• Lipopolysaccharides
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Receptor, PAR-2 (agonists, metabolism)
• Receptors, Cell Surface (physiology)