整合素α4β7与粘膜血管地址素细胞粘附分子-1(MAdCAM-1)之间的相互作用促进了炎症性肠病(IBD)中循环淋巴细胞与高内皮静脉表面的粘附。淋巴细胞粘附是涉及系链的多步骤级联反应,滚动,稳定的附着力,爬行,和细胞的迁移,整合素α4β7参与滚动和稳定的粘连。靶向整联蛋白α4β7-MAdCAM-1相互作用可能有助于减少IBD中的炎症。这种相互作用是由武力调节的;然而,潜在的机制仍然未知。这里,我们使用平行板流室和原子力显微镜研究这种机制。结果表明,整合素α4β7-MAdCAM-1相互作用的寿命最初增加,随后随着力的增加而减少。无论Ca2和/或Mg2的可用性如何,这都表现在通过捕获-粘结-滑移-粘结转化调节的两状态曲线中。相比之下,细胞的平均滚动速度最初随着力的增加而降低,然后增加,表明流动增强的附着力。在存在Mg2而不是Ca2的情况下,观察到单键的系链寿命更长,多键介导的滚动速度更低。当检查与用趋化因子CC基序配体25和MAdCAM-1共涂覆的基材的粘附性时,与用单独的MAdCAM-1涂覆的基材相反,获得类似的结果。总之,整联蛋白α4β7-MAdCAM-1相互作用通过离子和细胞因子依赖性流动增强的粘附过程发生,并通过捕获键机制调节。
The interaction between integrin α4β7 and mucosal vascular addressin cell-adhesion molecule-1 (MAdCAM-1) facilitates the adhesion of circulating lymphocytes to the surface of high endothelial venules in inflammatory bowel diseases (IBDs). Lymphocyte adhesion is a multistep cascade involving the tethering, rolling, stable adhesion, crawling, and migration of cells, with integrin α4β7 being involved in rolling and stable adhesions. Targeting the integrin α4β7-MAdCAM-1 interaction may help decrease inflammation in IBDs. This interaction is regulated by force; however, the underlying mechanism remains unknown. Here, we investigate this mechanism using a parallel plate flow chamber and atomic force microscopy. The results reveal an initial increase in the lifetime of the integrin α4β7-MAdCAM-1 interaction followed by a decrease with an increasing force. This was manifested in a two-state curve regulated via a catch-bond-slip-bond conversion regardless of Ca2+ and/or Mg2+ availability. In contrast, the mean rolling velocity of cells initially decreased and then increased with the increasing force, indicating the flow-enhanced adhesion. Longer tether lifetimes of single bonds and lower rolling velocities mediated by multiple bonds were observed in the presence of Mg2+ rather than Ca2+. Similar results were obtained when examining the adhesion to substrates co-coated with chemokine CC motif ligand 25 and MAdCAM-1, as opposed to substrates coated with MAdCAM-1 alone. In conclusion, the integrin α4β7-MAdCAM-1 interaction occurs via ion- and cytokine-dependent flow-enhanced adhesion processes and is regulated via a catch-bond mechanism.