Leukocyte rolling and adhesion via ICAM-1 signals to endothelial permeability. Focus on "Leukocyte rolling and adhesion both contribute to regulation of microvascular permeability to albumin via ligation of ICAM-1".
Leukocyte rolling and adhesion via ICAM-1 signals to endothelial permeability. Focus on "Leukocyte rolling and adhesion both contribute to regulation of microvascular permeability to albumin via ligation of ICAM-1".
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DOI：
10.1152/ajpcell.00250.2011
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发表时间：
2011-07
期刊：
影响因子：
--
通讯作者：
Marcie R. Williams;F. Luscinskas
中科院分区：
文献类型：
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作者：
Marcie R. Williams;F. Luscinskas
血管内皮通过诱导和表面表达粘附分子和趋化因子在炎症反应中起重要作用。在急性炎症部位，血流量增加，毛细血管后小静脉表现出渗透性增加（泄漏）并支持血液白细胞（主要是中性粒细胞）的流入。中性粒细胞流入和血管通透性增加之间的关系已经是几十年来的研究主题。许多研究报告了使用体内和体外模型在炎症期间血管通透性的直接嗜酸性粒细胞依赖性增加（综述见参考文献4）。已经得到越来越多的关注的一个方面是内皮细胞粘附分子是否有助于调节血管通透性，除了他们的良好的特点，在中性粒细胞滚动和粘附的作用。细胞间粘附分子-1（ICAM-1，也称为CD 54）是一种免疫球蛋白超家族成员，在内皮细胞表面大量表达，并在体内和体外内皮细胞边界富集（2，12，14，17）。ICAM-1表面表达在内皮细胞中被促炎细胞因子如TNF-、IL-1、IFN-或细菌内毒素上调，ICAM-1作为白细胞2-整联蛋白（LFA-1和Mac-1）的受体（综述见参考文献15）。在自然实验中，患有白细胞粘附缺陷-1（LAD-1）的患者具有严重的原发性免疫缺陷，其中血液中性粒细胞不能定位于炎症或损伤部位。这种缺陷的发生是因为患者的中性粒细胞缺乏2-整合素或这些分子中含有突变。使用来自LAD-1患者或2-整合素缺陷小鼠的中性粒细胞的研究清楚地表明，这些细胞在活化的内皮上具有正常的选择素依赖性滚动，但不能稳定地停滞和迁移。其他研究表明，内皮表达的ICAM-1有助于体内白细胞滚动和停滞的动力学，如通过ICAM-1 /小鼠提睾肌微循环的活体显微镜所测定的（16）。在本期《美国生理学-细胞生理学杂志》中，Sumagin及其同事（18）使用优雅的体内研究来证明提睾肌模型中的微血管通透性受ICAM-1的白细胞参与调节。作者通过荧光共聚焦活体显微镜监测提睾肌微循环的渗透性（Ps）。Sarelius及其同事（19）在同一模型中的先前研究表明，ICAM-1参与诱导未刺激的小动脉和TNF刺激的小静脉中血管通透性的局部增加。与这一发现一致，在相同条件下，与野生型（WT）小鼠相比，ICAM-1敲除（KO）动物中小动脉和小静脉的4 h TNF-刺激没有导致血管通透性增加。用2-整联蛋白KO小鼠观察到类似的结果。在目前的研究中，作者提供了进一步的证据，将ICAM-1表达与内皮通透性的调节联系起来。未受刺激的小静脉和TNF-处理的小静脉之间的比较表明，中性粒细胞滚动调节未受刺激的小静脉中的小静脉通透性，而白细胞粘附调节TNF-刺激的小静脉中的小静脉通透性。2-整联蛋白阻断抗体抑制内皮细胞上的中性粒细胞停滞，降低了血管通透性，并且这通过用2-整联蛋白和P-选择素阻断抗体的组合治疗进一步降低，所述2-整联蛋白和P-选择素阻断抗体抑制滚动和停滞。有趣的是，通过阻断P-选择素和β 2-整联蛋白功能观察到的小静脉通透性降低被认为是由于滚动白细胞的缺乏导致ICAM-1参与不足。为了检查中性粒细胞所起的作用，通过抗中性粒细胞GR-1抗体处理耗尽循环中性粒细胞。值得注意的是，中性粒细胞的耗竭引起了
THE VASCULAR ENDOTHELIUM plays a vital role in the inflammatory response by induction and surface expression of adhesion molecules and chemokines. At sites of acute inflammation, blood flow is increased and postcapillary venules exhibit increased permeability (leakiness) and support the influx of blood leukocytes, primarily neutrophils. The relationship between neutrophil influx and increased vessel permeability has been a topic of investigation for decades. Many investigations have reported a direct neutrophil-dependent increase in vessel permeability during inflammation using in vivo and in vitro models (reviewed in Ref. 4). One aspect that has received increased attention is whether endothelial cell adhesion molecules contribute to the regulation of vessel permeability, in addition to their well-characterized role in neutrophil rolling and adhesion. Intercellular adhesion molecule-1 (ICAM-1, also known as CD54) is an immunoglobulin superfamily member that is abundantly expressed on the endothelial cell surface and is enriched at endothelial cell borders in vivo and in vitro (2, 12, 14, 17). ICAM-1 surface expression is upregulated in endothelial cells by proinflammatory cytokines like TNF-, IL-1, IFN-, or bacterial endotoxins, and ICAM-1 serves as a receptor for leukocyte 2-integrins (LFA-1 and Mac-1) (reviewed in Ref. 15). In an experiment of nature, patients with leukocyte adhesion deficiency-1 (LAD-1) have a severe primary immune deficiency in which blood neutrophils fail to localize to sites of inflammation or injury. This defect occurs because patients’ neutrophils either lack 2-integrins or contain mutations in these molecules. Studies using neutrophils from LAD-1 patients or 2-integrin-deficient mice clearly demonstrate that these cells have normal selectin-dependent rolling on activated endothelium but fail to stably arrest and transmigrate. Additional studies have demonstrated that endothelial-expressed ICAM-1 contributes to both kinetics of leukocyte rolling and arrest in vivo as determined by intravital microscopy of the cremaster muscle microcirculation in ICAM-1 / mice (16). In this issue of American Journal of Physiology-Cell Physiology, Sumagin and colleagues (18) use elegant in vivo studies to demonstrate that microvascular permeability in the cremaster muscle model is regulated by leukocyte engagement of ICAM-1. The authors monitored permeability (Ps) in cremaster microcirculation by efflux of luminal fluorescent-tagged albumin by fluorescence confocal intravital microscopy. Prior studies by Sarelius and colleagues (19) in the same model demonstrated that ICAM-1 engagement induced a localized increase in vessel permeability in unstimulated arterioles and in TNF-stimulated venules. In agreement with this finding ,4ho f TNF- stimulation of arterioles and venules in ICAM-1 knockout (KO) animals did not result in increased vessel permeability as compared with wild-type (WT) mice under identical conditions. Similar results were seen with 2-integrin KO mice. In the current study, the authors provide further evidence linking ICAM-1 expression to regulation of endothelial permeability. Comparisons between unstimulated venules and TNF--treated venules reveal that neutrophil rolling regulates venule permeability in unstimulated venules while leukocyte adhesion regulates venule permeability in TNF--stimulated venules. The 2-integrin-blocking antibodies, which inhibit neutrophil arrest on endothelium, reduced the vessel permeability, and this was further reduced by treatment with a combination of 2-integrin and P-selectin blocking antibodies that inhibits both rolling and arrest. Interestingly, the reduction in venule permeability observed by blockade of P-selectin and 2-integrin function were suggested to be due to insufficient ICAM-1 engagement due to the absence of rolling leukocytes. To examine the role that neutrophils play, circulating neutrophils were depleted by antineutrophil GR-1 antibody treatment. Notably, depletion of neutrophils caused a marked decrease in