Investigation of Fascin1, a Marker of Mature Dendritic Cells, Reveals a New Role for IL-6 Signaling in CCR7-Mediated Chemotaxis.
Investigation of Fascin1, a Marker of Mature Dendritic Cells, Reveals a New Role for IL-6 Signaling in CCR7-Mediated Chemotaxis.
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DOI：
10.4049/jimmunol.2000318
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发表时间：
2021-08-01
期刊：
影响因子：
--
通讯作者：
Yamashiro S
中科院分区：
文献类型：
--
作者：
Matsumura F;Polz R;Singh S;Matsumura A;Scheller J;Yamashiro S
成熟树突状细胞（DC）向淋巴结的迁移对于启动适应性免疫至关重要。CCR 7是CCL 19/21趋化因子的G蛋白偶联受体，已知其对成熟DC的趋化性是必需的，但将炎症与趋化性联系起来的分子机制仍不清楚。我们以前证明，fascin 1，肌动蛋白捆绑蛋白，增加成熟小鼠树突状细胞的趋化性。在本文中，我们证明fascin 1增强白细胞介素（IL）-6分泌和成熟的小鼠树突状细胞的信号。此外，我们证明了IL-6信号是趋化性所必需的。用抗IL-6受体α（IL-6 R α）抗体阻断WT DC中的IL-6信号传导可抑制对CCL 19的趋化性。同样地，IL-6 R α的敲除（KO）抑制骨髓来源的DC（BMDC）的趋化性。可溶性IL-6 R α和IL-6的加入挽救了IL-6 R α KO BMDC的趋化性，强调了IL-6信号传导在趋化性中的作用。我们发现，IL-6信号转导是CCR 7内化所必需的，这是CCR 7再循环的初始步骤。CCR 7再循环对于CCR 7介导的趋化性是必不可少的，这解释了为什么IL-6信号传导对于成熟DC的趋化性是必需的。我们的研究结果表明，IL-6信号作为一种新的调节途径CCR 7/CCL 19介导的趋化性，并表明，成熟的DC快速迁移到淋巴结依赖于炎症相关的IL-6信号。
Migration of mature dendritic cells (DCs) to lymph nodes is critical for the initiation of adaptive immunity. CCR7, a G-protein-coupled receptor for CCL19/21 chemokines, is known to be essential for chemotaxis of mature DCs, but the molecular mechanism linking inflammation to chemotaxis remains unclear. We previously demonstrated that fascin1, an actin-bundling protein, increases chemotaxis of mature mouse DCs. In this paper we demonstrated that fascin1 enhanced Interleukin (IL)-6 secretion and signaling of mature mouse DCs. Furthermore, we demonstrated that IL-6 signaling is required for chemotaxis. Blockage of IL-6 signaling in WT DCs with an anti-IL-6 receptorα (IL-6Rα) antibody inhibited chemotaxis toward CCL19. Likewise, knockout (KO) of IL-6Rα inhibited chemotaxis of bone marrow-derived DCs (BMDCs). The addition of soluble IL-6Rα and IL-6 rescued chemotaxis of IL-6Rα KO BMDCs, underscoring the role of IL-6 signaling in chemotaxis. We found that IL-6 signaling is required for internalization of CCR7, the initial step of CCR7 recycling. CCR7 recycling is essential for CCR7-mediated chemotaxis, explaining why IL-6 signaling is required for chemotaxis of mature DCs. Our results have identified IL-6 signaling as a new regulatory pathway for CCR7/CCL19-mediated chemotaxis, and suggest that rapid migration of mature DCs to lymph nodes depends on inflammation-associated IL-6 signaling.
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