School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China.
Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, South China University of Technology, Guangzhou 510006, China.
Int J Mol Sci. 2023 Nov 7;24(22):16062. doi: 10.3390/ijms242216062.
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 Ca and/or Mg 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 Mg rather than Ca. 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.
整合素 α4β7 与黏膜血管地址素细胞黏附分子-1（MAdCAM-1）之间的相互作用促进了循环淋巴细胞与炎症性肠病（IBD）中高内皮小静脉表面的黏附。淋巴细胞黏附是一个多步骤级联反应，涉及细胞的系留、滚动、稳定黏附、爬行和迁移，整合素 α4β7 参与滚动和稳定黏附。靶向整合素 α4β7-MAdCAM-1 相互作用可能有助于减少 IBD 中的炎症。这种相互作用受力学调节；然而，其潜在机制尚不清楚。在这里，我们使用平行板流动室和原子力显微镜研究了这种机制。结果表明，整合素 α4β7-MAdCAM-1 相互作用的寿命最初增加，然后随着力的增加而减少。这表现为通过捕获键-滑动键转换调节的两态曲线，无论 Ca 和/或 Mg 是否存在。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，表明流动增强了黏附。在存在 Mg 而不是 Ca 的情况下，观察到单键的更长系留寿命和多键介导的较低滚动速度。当研究与趋化因子 CC 基序配体 25 和 MAdCAM-1 共涂覆的底物而不是单独涂覆 MAdCAM-1 的底物的黏附时，获得了类似的结果。总之，整合素 α4β7-MAdCAM-1 相互作用通过离子和细胞因子依赖的流动增强黏附过程发生，并通过捕获键机制进行调节。
