Defect in regulated secretion of P-selectin affects leukocyte recruitment in von Willebrand factor-deficient mice
Defect in regulated secretion of P-selectin affects leukocyte recruitment in von Willebrand factor-deficient mice
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DOI：
10.1073/pnas.061307098
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发表时间：
2001-03-27
影响因子：
11.1
通讯作者：
Wagner, DD
中科院分区：
文献类型：
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作者：
Denis, CV;André, P;Wagner, DD
各种炎症介质对内皮细胞的刺激导致韦贝尔-帕拉德小体的释放，从而导致p -选择素（白细胞粘附受体）和血管性血液病因子（vWf）（血小板配体）的分泌。利用vWf缺陷小鼠研究了vWf在白细胞募集中的潜在作用。我们报告了vwf缺陷小鼠小静脉中白细胞滚动的强烈减少。同样，在细胞因子诱导的脑膜炎模型和早期皮肤创伤中，vWf缺乏导致中性粒细胞募集减少。在所有具有优先识别质膜p -选择素的抗体的情况下，我们观察到vWf缺陷内皮细胞表面p -选择素的表达显著降低。通过共聚焦显微镜，我们发现vWf- /-内皮细胞中缺少典型的weihelpalade体棒状结构，并且vWf- /-细胞中部分p -选择素含量与LAMP-1（溶酶体标记物）共定位。然而，两种基因型的肿瘤坏死因子α和脂多糖激活细胞内p -选择素水平相似，我们得出结论，vWf的缺乏，如在严重血管性血肿病中发现的那样，导致韦贝尔-帕拉德体形成缺陷。这种缺陷导致p -选择素转移到细胞表面的减少和炎症早期白细胞募集的减少。
Stimulation of endothelial cells by various inflammatory mediators leads to release of Weibel-Palade bodies and therefore to exocytosis of both P-selectin (adhesion receptor for leukocytes) and von Willebrand factor (vWf) (platelet ligand), The potential role of vWf in leukocyte recruitment was investigated with the use of vWf-deficient mice. We report a strong reduction of leukocyte rolling in venules of vWf-deficient mice. Similarly, vWf deficiency led to a decrease in neutrophil recruitment in a cytokine-induced meningitis model as well as in early skin wounds. In all instances with an antibody that preferentially recognizes plasma membrane P-selectin, we observed a dramatic reduction in P-selectin expression at the cell surface of vWf-deficient endothelium, With confocal microscopy, we found that the typical rodlike shape of the Weihel-Palade body is missing in vWf -/- endothelial cells and that part of the P-selectin content in the vWf -/- cells colocalized with LAMP-1, a lysosomal marker. However, intracellular P-selectin levels were similar in tumor necrosis factor alpha- and lipopolysaccharide-activated cells of both genotypes, We conclude that the absence of vWf, as found in severe von Willebrand disease, leads to a defect in Weibel-Palade body formation. This defect results in decreased P-selectin translocation to the cell surface and reduced leukocyte recruitment in early phases of inflammation.