1] Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, and Interdisciplinary Clinical Research Center, University of Münster, von-Esmarch Strasse 56, 48149 Münster, Germany [2].
1] Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany [2] Department of Vascular Cell Biology, Max-Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
Nat Commun. 2014 Apr 28;5:3738. doi: 10.1038/ncomms4738.
To enable leukocyte adhesion to activated endothelium, the leukocyte receptor P-selectin is released from Weibel-Palade bodies (WPB) to the endothelial cell surface where it is stabilized by CD63. Here we report that loss of annexin A8 (anxA8) in human umbilical vein endothelial cells (HUVEC) strongly decreases cell surface presentation of CD63 and P-selectin, with a concomitant reduction in leukocyte rolling and adhesion. We confirm the compromised leukocyte adhesiveness in inflammatory-activated endothelial venules of anxA8-deficient mice. We find that WPB of anxA8-deficient HUVEC contain less CD63, and that this is caused by improper transport of CD63 from late multivesicular endosomes to WPB, with CD63 being retained in intraluminal vesicles. Consequently, reduced CD63 cell surface levels are seen following WPB exocytosis, resulting in enhanced P-selectin re-internalization. Our data support a model in which anxA8 affects leukocyte recruitment to activated endothelial cells by supplying WPB with sufficient amounts of the P-selectin regulator CD63.
为了使白细胞黏附在活化的内皮细胞上，白细胞受体 P 选择素从 Weibel-Palade 小体 (WPB) 释放到内皮细胞表面，在那里它被 CD63 稳定。在这里，我们报告说，人脐静脉内皮细胞 (HUVEC) 中 annexin A8 (anxA8) 的缺失强烈降低了 CD63 和 P 选择素在细胞表面的呈现，伴随着白细胞滚动和黏附的减少。我们证实了 anxA8 缺陷型小鼠炎症激活的内皮小静脉中白细胞黏附功能受损。我们发现 anxA8 缺陷型 HUVEC 的 WPB 中含有较少的 CD63，这是由于 CD63 从晚期多泡内体向 WPB 的运输不当，导致 CD63 在内腔小泡中滞留。因此，在 WPB 胞吐作用后，细胞表面的 CD63 水平降低，导致 P 选择素的再内化增强。我们的数据支持这样一种模型，即 anxA8 通过向 WPB 提供足够数量的 P 选择素调节因子 CD63 ，影响白细胞募集到活化的内皮细胞。
