Dendritic cell entry to lymphatic capillaries is orchestrated by CD44 and the hyaluronan glycocalyx.
Dendritic cell entry to lymphatic capillaries is orchestrated by CD44 and the hyaluronan glycocalyx.
复制标题
DOI：
10.26508/lsa.202000908
复制
发表时间：
2021-05
影响因子：
4.4
通讯作者：
Jackson DG
中科院分区：
文献类型：
--
作者：
Johnson LA;Banerji S;Lagerholm BC;Jackson DG
CD44将透明质酸糖萼锚定在迁移的树突状细胞上，允许与内皮受体LYVE-1对接，从而通过调节糖萼密度来协调淋巴运输。树突状细胞通过传入淋巴管将抗原从外周组织输送到引流淋巴结，在免疫中发挥重要作用。该过程的关键是通过DC表面的配体透明质酸与淋巴内皮受体LYVE-1初始对接。然而，这种相对弱的结合聚合物是如何被配置成与LYVE-1特异性粘附的，目前尚不清楚。在这里，我们发现透明质酸被白细胞受体CD44锚定并在空间上组织成一个400-500纳米的致密糖萼。通过基因敲除和调节CD44-透明质酸与单克隆抗体的相互作用，在体外和恶唑酮诱导的皮肤炎症小鼠模型中，我们证明了CD44是DC粘附和淋巴内皮转运所必需的。此外，我们提供的证据表明，CD44可以动态控制透明质酸糖萼的密度，调节DC向淋巴结的运输效率。我们的研究结果确定了CD44在淋巴运输中以前未被认识到的作用，并强调了CD44:HA:LYVE-1轴在其调节中的重要性。
CD44 anchors the hyaluronan glycocalyx on migrating dendritic cells to permit docking to the endothelial receptor LYVE-1, thus orchestrating lymphatic trafficking through modulating glycocalyx density. DCs play a vital role in immunity by conveying antigens from peripheral tissues to draining lymph nodes, through afferent lymphatic vessels. Critical to the process is initial docking to the lymphatic endothelial receptor LYVE-1 via its ligand hyaluronan on the DC surface. How this relatively weak binding polymer is configured for specific adhesion to LYVE-1, however, is unknown. Here, we show that hyaluronan is anchored and spatially organized into a 400–500 nm dense glycocalyx by the leukocyte receptor CD44. Using gene knockout and by modulating CD44-hyaluronan interactions with monoclonal antibodies in vitro and in a mouse model of oxazolone-induced skin inflammation, we demonstrate that CD44 is required for DC adhesion and transmigration across lymphatic endothelium. In addition, we present evidence that CD44 can dynamically control the density of the hyaluronan glycocalyx, regulating the efficiency of DC trafficking to lymph nodes. Our findings define a previously unrecognized role for CD44 in lymphatic trafficking and highlight the importance of the CD44:HA:LYVE-1 axis in its regulation.