Impaired Transmigration of Myeloid-Derived Suppressor Cells across Human Sinusoidal Endothelium Is Associated with Decreased Expression of CD13
Impaired Transmigration of Myeloid-Derived Suppressor Cells across Human Sinusoidal Endothelium Is Associated with Decreased Expression of CD13
复制标题
DOI：
10.4049/jimmunol.1600466
复制
发表时间：
2017-09
期刊：
影响因子：
--
通讯作者：
Y. Resheq;Ann-Katrin Menzner;J. Bosch;J. Tickle;K. Li;A. Wilhelm;E. Hepburn;Gillian Murihead;S. Ward;S. Curbishley;H. Zimmermann;Tony Bruns;Daniel F Gilbert;P. Tripal;A. Mackensen;D. Adams;C. Weston
中科院分区：
文献类型：
--
作者：
Y. Resheq;Ann-Katrin Menzner;J. Bosch;J. Tickle;K. Li;A. Wilhelm;E. Hepburn;Gillian Murihead;S. Ward;S. Curbishley;H. Zimmermann;Tony Bruns;Daniel F Gilbert;P. Tripal;A. Mackensen;D. Adams;C. Weston
人单核细胞髓源性抑制细胞（MO-MDSCs）在肝癌中抑制炎症并损害免疫监视。目前尚不清楚通过肝窦内皮（HSEC）从血液中募集的MO-MDSCs是否有助于它们在肝室内的富集。我们通过模拟活体窦内剪切应力的流动实验，比较了MO-MDSCs和单核细胞粘附到肝内皮单层后的移行潜力。尽管与HSEC单层的结合相当，但MO-MDSCs进行跨内皮迁移的比例较少，这表明在肌动蛋白聚合起重要作用的外渗的最后步骤在MO-MDSCs中受到损害。在这篇文章中，我们发现MO-MDSCs的CD13水平降低，这最近被报道控制单核细胞的细胞运动，同时降低了vla4的表达，这是一种主要参与内皮顶端粘附的整合素。CD13和VLA-4阻断和激活抗体被用于基于流动的粘附实验、活细胞运动成像和肌动蛋白聚合研究，以证实CD13在MO-MDSC转运受损中的作用。这些发现表明，CD13显著促进了MO-MDSCs和单核细胞的组织浸润，从而参与了肝脏炎症的发病机制。
Human monocytic myeloid-derived suppressor cells (MO-MDSCs) within the hepatic compartment suppress inflammation and impair immune surveillance in liver cancer. It is currently not known whether recruitment of MO-MDSCs from blood via hepatic sinusoidal endothelium (HSEC) contributes to their enrichment within the hepatic compartment. We compared the transmigratory potential of MO-MDSCs and monocytes after adhesion to hepatic endothelial monolayers in flow-based assays that mimic in vivo shear stress in the sinusoids. Despite comparable binding to HSEC monolayers, proportionally fewer MO-MDSCs underwent transendothelial migration, indicating that the final steps of extravasation, where actin polymerization plays an important role, are impaired in MO-MDSCs. In this article, we found reduced levels of CD13 on MO-MDSCs, which has recently been reported to control cell motility in monocytes, alongside reduced VLA-4 expression, an integrin predominantly involved in adherence to the apical side of the endothelium. CD13 and VLA-4 blocking and activating Abs were used in flow-based adhesion assays, live-cell imaging of motility, and actin polymerization studies to confirm a role for CD13 in impaired MO-MDSC transmigration. These findings indicate that CD13 significantly contributes to tissue infiltration by MO-MDSCs and monocytes, thereby contributing to the pathogenesis of hepatic inflammation.