SCARB2/LIMP-2 Regulates IFN Production of Plasmacytoid Dendritic Cells by Mediating Endosomal Translocation of TLR9 and Nuclear Translocation of IRF7.
SCARB2/LIMP-2 Regulates IFN Production of Plasmacytoid Dendritic Cells by Mediating Endosomal Translocation of TLR9 and Nuclear Translocation of IRF7.
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DOI：
10.4049/jimmunol.1402312
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发表时间：
2015-05-15
期刊：
影响因子：
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通讯作者：
Zhang L
中科院分区：
文献类型：
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作者：
Guo H;Zhang J;Zhang X;Wang Y;Yu H;Yin X;Li J;Du P;Plumas J;Chaperot L;Chen J;Su L;Liu Y;Zhang L
清道夫受体B类成员2（SCARB 2）对于内体生物发生和重组是必需的，并且作为β-葡糖脑苷脂酶和肠道病毒71的受体。然而，人们对其在先天免疫细胞中的功能知之甚少。在这项研究中，我们表明，在人类外周血细胞中，SCARB 2是最高度表达的浆细胞样树突状细胞（pDC），其表达进一步上调CpG寡脱氧核苷酸刺激。pDC细胞系GEN2.2中SCARB 2的敲低显著降低CpG诱导的I型IFN产生。详细的研究显示SCARB 2定位于pDC的晚期内体/溶酶体，并且SCARB 2的敲低不影响CpG寡核苷酸摄取，但导致TLR9在内质网中的保留和IFN调节因子7的核转位受损。通过TLR7配体刺激产生的IFN-I也受到SCARB 2敲低的损害。然而，SCARB 2对于流感病毒或HSV诱导的IFN-I产生不是必需的。这些发现表明SCARB 2通过介导TLR9的内体易位和IFN调节因子7的核易位来调节pDC的TLR9依赖性IFN-1产生。
Scavenger receptor class B, member 2 (SCARB2) is essential for endosome biogenesis and reorganization and serves as a receptor for both β-glucocerebrosidase and enterovirus 71. However, little is known about its function in innate immune cells. In this study, we show that, among human peripheral blood cells, SCARB2 is most highly expressed in plasmacytoid dendritic cells (pDCs), and its expression is further upregulated by CpG oligodeoxynucleotide stimulation. Knockdown of SCARB2 in pDC cell line GEN2.2 dramatically reduces CpG-induced type I IFN production. Detailed studies reveal that SCARB2 localizes in late endosome/lysosome of pDCs, and knockdown of SCARB2 does not affect CpG oligodeoxynucleotide uptake but results in the retention of TLR9 in the endoplasmic reticulum and an impaired nuclear translocation of IFN regulatory factor 7. The IFN-I production by TLR7 ligand stimulation is also impaired by SCARB2 knockdown. However, SCARB2 is not essential for influenza virus or HSV-induced IFN-I production. These findings suggest that SCARB2 regulates TLR9-dependent IFN-I production of pDCs by mediating endosomal translocation of TLR9 and nuclear translocation of IFN regulatory factor 7.