EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice. Blood 2015 Apr 30;125(18):2845-54
Date
03/04/2015Pubmed ID
25733582Pubmed Central ID
PMC4424632DOI
10.1182/blood-2014-11-610717Scopus ID
2-s2.0-84946801346 (requires institutional sign-in at Scopus site) 62 CitationsAbstract
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.
Author List
Liang HP, Kerschen EJ, Hernandez I, Basu S, Zogg M, Botros F, Jia S, Hessner MJ, Griffin JH, Ruf W, Weiler HAuthors
Martin J. Hessner PhD Professor in the Pediatrics department at Medical College of WisconsinHartmut Weiler PhD Associate Professor in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBlood Coagulation
Blood Coagulation Factors
Cells, Cultured
Endothelial Protein C Receptor
Endotoxemia
Gene Expression Regulation
Interferons
Lipopolysaccharides
Mice
Mice, Inbred C57BL
Mice, Knockout
Receptor, PAR-2
Receptors, Cell Surface