Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice
Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice
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DOI：
10.1172/jci42629
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发表时间：
2010-09-01
影响因子：
15.9
通讯作者：
Weiler, Hartmut
中科院分区：
文献类型：
--
作者：
Kerschen, Edward;Hernandez, Irene;Weiler, Hartmut
活化蛋白C（aPC）治疗可降低严重脓毒症成人患者的死亡率。在小鼠内毒素血症和脓毒症模型中，死亡率降低需要aPC的细胞信号传导功能，其通过蛋白酶激活受体-1（PAR 1）和内皮蛋白C受体（EPCR;也称为Procr）介导。aPC的候选细胞靶标包括血管内皮细胞和白细胞。在这里，我们表明，造血细胞上的EPCR和PAR 1的表达是需要在小鼠中的aPC的变体，介导完整的细胞信号传导活性，但只有最小的抗凝功能（5A-aPC），以减少内毒素血症的死亡率。EPCR在成熟鼠免疫细胞中的表达仅限于CD 8（+）常规树突状细胞的亚群。将野生型小鼠脾脏CD 11 c（hi）PDCA-1（-）树突状细胞连续转移到造血EPCR缺陷动物中，可恢复aPC的治疗效果，而转移EPCR缺陷的CD 11 c（hi）树突状细胞或去除EPCR+细胞的野生型CD 11 c（hi）树突状细胞则不能。此外，5A-aPC抑制不依赖于EPCR的常规树突状细胞的炎症反应，并抑制天然树突状细胞样树突状细胞的IFN-γ产生。这些数据揭示了EPCR和PAR 1对造血细胞的重要作用，鉴定了表达EPCR的树突状免疫细胞作为aPC治疗的关键靶标，并记录了aPC对先天性免疫细胞的EPCR非依赖性免疫效应。
Activated protein C (aPC) therapy reduces mortality in adult patients with severe sepsis. In mouse endotoxemia and sepsis models, mortality reduction requires the cell signaling function of aPC, mediated through protease-activated receptor-1 (PAR1) and endothelial protein C receptor (EPCR; also known as Procr). Candidate cellular targets of aPC include vascular endothelial cells and leukocytes. Here, we show that expression of EPCR and PAR1 on hematopoietic cells is required in mice for an aPC variant that mediates full cell signaling activity but only minimal anticoagulant function (5A-aPC) to reduce the mortality of endotoxemia. Expression of EPCR in mature murine immune cells was limited to a subset of CD8(+) conventional dendritic cells. Adoptive transfer of splenic CD11c(hi)PDCA-1(-) dendritic cells from wild-type mice into animals with hematopoietic EPCR deficiency restored the therapeutic efficacy of aPC, whereas transfer of EPCR-deficient CD11c(hi) dendritic cells or wild-type CD11c(hi) dendritic cells depleted of EPCR+ cells did not. In addition, 5A-aPC inhibited the inflammatory response of conventional dendritic cells independent of EPCR and suppressed IFN-gamma production by natural killer-like dendritic cells. These data reveal an essential role for EPCR and PAR1 on hematopoietic cells, identify EPCR-expressing dendritic immune cells as a critical target of aPC therapy, and document EPCR-independent antiinflammatory effects of aPC on innate immune cells.