EBI2 is a negative regulator of type I interferons in plasmacytoid and myeloid dendritic cells.
EBI2 is a negative regulator of type I interferons in plasmacytoid and myeloid dendritic cells.
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DOI：
10.1371/journal.pone.0083457
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Grogan JL
中科院分区：
文献类型：
--
作者：
Chiang EY;Johnston RJ;Grogan JL
EB病毒诱导受体2(EBI2)是一种GαI偶联的G蛋白偶联受体，是B、T细胞和树突状细胞(DC)的趋化受体。遗传学研究也表明EBI2是干扰素调节因子7(IRF7)驱动的炎症网络(IDIN)的调节因子，与自身免疫性疾病相关，尽管尚未报道初级I型干扰素产生细胞的必然结果。在这里，我们证明了EBI2负性调节浆细胞样树突状细胞(PDCs)和CD11b+髓系细胞的I型干扰素反应。与野生型细胞相比，EBI2TLRpDC和CD11b+细胞被不同的−/−配体激活后，I型干扰素的产生增加。此外，与正常小鼠相比，体内用内毒素受体激动剂或感染淋巴细胞性脉络膜脑膜炎病毒可诱导更多的I型干扰素和促炎细胞因子。尽管EBI2缺陷的PDCs和CD11b+细胞在体内平衡条件下从血液迁移到脾和腹膜的能力受损，但全身细胞因子仍然升高。据报道，对于其他免疫细胞，pDC的迁移依赖于EBI2，7α，25-二羟基胆固醇的配体。EBI2缺陷小鼠的I型干扰素产生细胞表达较高水平的IRF7和IDIN基因，这与EBI2的细胞固有作用一致。综上所述，这些数据表明，EBI2在平衡TLR介导的对可能引发自身免疫的外源和自身核酸的反应方面发挥了负面调节作用。
Epstein-Barr virus induced receptor 2 (EBI2), a Gαi-coupled G protein-coupled receptor, is a chemotactic receptor for B, T and dendritic cells (DC). Genetic studies have also implicated EBI2 as a regulator of an interferon regulatory factor 7 (IRF7)-driven inflammatory network (IDIN) associated with autoimmune diseases, although the corollary in primary type I IFN-producing cells has not been reported. Here we demonstrate that EBI2 negatively regulates type I IFN responses in plasmacytoid DC (pDCs) and CD11b+ myeloid cells. Activation of EBI2−/− pDCs and CD11b+ cells with various TLR ligands induced elevated type I IFN production compared to wild-type cells. Moreover, in vivo challenge with endosomal TLR agonists or infection with lymphocytic choriomeningitis virus elicited more type I IFNs and proinflammatory cytokines in EBI2−/− mice compared to normal mice. Elevated systemic cytokines occurred despite impaired ability of EBI2-deficient pDCs and CD11b+ cells to migrate from the blood to the spleen and peritoneal cavity under homeostatic conditions. As reported for other immune cells, pDC migration was dependent on the ligand for EBI2, 7α,25-dihydroxycholesterol. Consistent with a cell intrinsic role for EBI2, type I IFN-producing cells from EBI2-deficient mice expressed higher levels of IRF7 and IDIN genes. Together these data suggest a negative regulatory role for EBI2 in balancing TLR-mediated responses to foreign and to self nucleic acids that may precipitate autoimmunity.
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