EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice
EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice
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DOI：
10.1182/blood-2014-11-610717
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发表时间：
2015-04-30
期刊：
影响因子：
20.3
通讯作者：
Weiler, Hartmut
中科院分区：
文献类型：
--
作者：
Liang, Hai Po H.;Kerschen, Edward J.;Weiler, Hartmut
感染和炎症总是与凝血机制的激活有关，其次是炎症诱导的凝血启动因子(TF)在先天免疫细胞上的表达。通过研究细胞表面凝血因子受体在小鼠内毒素血症中的作用，我们发现蛋白C受体(proR；EPCR)是正常的体内和体外诱导内毒素(LPS)调节的基因表达所必需的。在培养的骨髓髓系细胞和单核细胞RAW264.7中，内毒素诱导的功能性Tf的表达，凝血的三元Tf-VIIa-Xa起始复合体的组装，以及三元Tf-VIIa-Xa复合体依赖于EPCR激活的蛋白酶激活受体2(PAR2)，是正常诱导编码TLR3/4信号转导蛋白Pellino-1和转录因子干扰素调节因子8的信使RNA所必需的。GBP3和GBP6。因此，炎症诱导的TF表达以及与EPCR、PAR2和TLR4的串扰似乎对于干扰素调节的宿主反应的正常进化是必要的。
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.