Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan; Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
EBioMedicine. 2017 Oct;24:247-256. doi: 10.1016/j.ebiom.2017.09.012. Epub 2017 Sep 14.
CXCL14 is a primordial chemokine that plays multiple roles in tumor suppression, autoimmune arthritis, and obesity-associated insulin resistance. However, the underlying molecular mechanisms are unclear. Here, we show that CXCL14 transports various types of CpG oligodeoxynucleotide (ODN) into the endosomes and lysosomes of bone marrow-derived dendritic cells (DCs), thereby activating Toll-like receptor 9 (TLR9). A combination of CpG ODN (ODN2395) plus CXCL14 induced robust production of IL-12 p40 by wild-type, but not Tlr9-knockout, DCs. Consistent with this, ODN2395-mediated activation of DCs was significantly attenuated in Cxcl14-knockout mice. CXCL14 bound CpG ODN with high affinity at pH7.5, but not at pH6.0, thereby enabling efficient delivery of CpG ODN to TLR9 in the endosome/lysosome. Furthermore, the CXCL14-CpG ODN complex specifically bound to high affinity CXCL14 receptors on DCs. Thus, CXCL14 serves as a specific carrier of CpG DNA to sensitize TLR9-mediated immunosurveillance.
CXCL14 是一种原始趋化因子，在肿瘤抑制、自身免疫性关节炎和肥胖相关胰岛素抵抗中发挥多种作用。然而，其潜在的分子机制尚不清楚。在这里，我们表明 CXCL14 将多种类型的 CpG 寡脱氧核苷酸 (ODN) 转运到骨髓来源的树突状细胞 (DC) 的内体和溶酶体中，从而激活 Toll 样受体 9 (TLR9)。CpG ODN (ODN2395) 与 CXCL14 的组合诱导野生型，但不是 Tlr9 敲除型，DC 产生大量的 IL-12 p40。与此一致的是，在 Cxcl14 敲除小鼠中，ODN2395 介导的 DC 激活明显减弱。CXCL14 在 pH7.5 时与 CpG ODN 具有高亲和力结合，但在 pH6.0 时不结合，从而能够将 CpG ODN 有效递送至内体/溶酶体中的 TLR9。此外，CXCL14-CpG ODN 复合物特异性结合 DC 上的高亲和力 CXCL14 受体。因此，CXCL14 可作为 CpG DNA 的特异性载体，增强 TLR9 介导的免疫监视。
