Mucin-Like Domain of Mucosal Addressin Cell Adhesion Molecule-1 Facilitates Integrin α4β7-Mediated Cell Adhesion Through Electrostatic Repulsion.
Mucin-Like Domain of Mucosal Addressin Cell Adhesion Molecule-1 Facilitates Integrin α4β7-Mediated Cell Adhesion Through Electrostatic Repulsion.
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粘膜寻址细胞粘附分子-1的粘蛋白样结构域通过静电排斥促进整合素α4β7介导的细胞粘附
DOI：
10.3389/fcell.2020.603148
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发表时间：
2020
影响因子：
5.5
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Yuan M;Yang Y;Li Y;Yan Z;Lin C;Chen J
淋巴细胞从血液到肠道相关淋巴组织的归巢受到整合素α4β7与高内皮微静脉（HEVs）内皮上表达的粘膜血管地址素细胞粘附分子1（MAdCAM-1）之间的相互作用的调节。然而，MAdCAM-1调节整合素α4β7介导的细胞粘附的特异性结构粘蛋白样结构域的分子基础仍然不清楚。本研究利用硫酸乙酰肝素（HS）模拟细胞外微环境的负电荷，检测表达整合素α4β7的293 T细胞对固定化MAdCAM-1的粘附行为。结果表明，HS能显著促进整合素α4β7介导的细胞粘附，降低细胞牢固结合的比例，并提高高切应力下的滚动速度，这与MAdCAM-1的粘蛋白样结构域有关。此外，用唾液酸酶破坏表达MAdCAM-1的CHO-K1细胞的细胞外微环境的负电荷抑制293 T细胞的细胞粘附和滚动速度。从机制上讲，粘蛋白样结构域与细胞外微环境的负电荷之间的静电排斥导致MAdCAM-1的更直立的构象，这有助于整合素α4β7介导的细胞粘附。我们的研究结果阐明了粘蛋白样结构域在调节整合素α4β7介导的细胞粘附中的重要作用，其可用于调节淋巴细胞归巢至淋巴组织或炎症部位。
The homing of lymphocytes from blood to gut-associated lymphoid tissue is regulated by interaction between integrin α4β7 with mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) expressed on the endothelium of high endothelial venules (HEVs). However, the molecular basis of mucin-like domain, a specific structure of MAdCAM-1 regulating integrin α4β7-mediated cell adhesion remains obscure. In this study, we used heparan sulfate (HS), which is a highly acidic linear polysaccharide with a highly variable structure, to mimic the negative charges of the extracellular microenvironment and detected the adhesive behaviors of integrin α4β7 expressing 293T cells to immobilized MAdCAM-1 in vitro. The results showed that HS on the surface significantly promoted integrin α4β7-mediated cell adhesion, decreased the percentage of cells firmly bound and increased the rolling velocities at high wall shear stresses, which was dependent on the mucin-like domain of MAdCAM-1. Moreover, breaking the negative charges of the extracellular microenvironment of CHO-K1 cells expressing MAdCAM-1 with sialidase inhibited cell adhesion and rolling velocity of 293T cells. Mechanistically, electrostatic repulsion between mucin-like domain and negative charges of the extracellular microenvironment led to a more upright conformation of MAdCAM-1, which facilitates integrin α4β7-mediated cell adhesion. Our findings elucidated the important role of the mucin-like domain in regulating integrin α4β7-mediated cell adhesion, which could be applied to modulate lymphocyte homing to lymphoid tissues or inflammatory sites.
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