Mucin-Like Domain of Mucosal Addressin Cell Adhesion Molecule-1 Facilitates Integrin α4β7-Mediated Cell Adhesion Through Electrostatic Repulsion.

Mengya Yuan,Yue Li,Zhanjun Yan,Changdong Lin,Yanrong Yang,Jianfeng Chen

doi:10.3389/fcell.2020.603148

Abstract

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.

Highlights

Integrins are important cell surface adhesion molecules, which are widely expressed on the cell membrane
The results showed that heparan sulfate (HS) on the surface promoted integrin α4β7-mediated cell adhesion to immobilized MAdCAM-1, which was dependent on the mucin-like domain of MAdCAM-1
These data demonstrate that HS on the surface promotes integrin α4β7-mediated cell adhesion to immobilized MAdCAM-1, which might be due to the negative charges of sulfate groups in HS chains

Summary

Introduction

Integrins are important cell surface adhesion molecules, which are widely expressed on the cell membrane. A highly ordered adhesion cascade mediates the recruitment process, including tethering and rolling of lymphocytes along vessel walls of HEVs, chemokine-induced integrin activation, firm arrest and transendothelial migration (von Andrian and Mempel, 2003; Lin et al, 2019). During this process, α4 integrins (α4β1 and α4β7) and β2 integrins (e.g., αLβ2 and αMβ2) on lymphocytes bind to their distinct ligands on vascular endothelial cells to mediate cell adhesion and migration. Α4 integrins, especially integrin α4β7 mediates both rolling and firm adhesion to mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) (Berlin et al, 1993; Sun et al, 2014; Wang et al, 2018), which plays an important role to support efficient lymphocyte homing

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