Aberrant activation of integrin α4β7 suppresses lymphocyte migration to the gut
Eun Jeong Park, … , Ulrich H. von Andrian, Motomu Shimaoka
Eun Jeong Park, … , Ulrich H. von Andrian, Motomu Shimaoka
Published September 4, 2007
Citation Information: J Clin Invest. 2007;117(9):2526-2538. https://doi.org/10.1172/JCI31570.
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Research Article

Aberrant activation of integrin α4β7 suppresses lymphocyte migration to the gut

Abstract

Integrin adhesion molecules mediate lymphocyte migration and homing to normal and inflamed tissues. While the ligand-binding activity of integrins is known to be modulated by conformational changes, little is known about how the appropriate balance of integrin adhesiveness is maintained in order to optimize the migratory capacity of lymphocytes in vivo. In this study we examined the regulation of the gut homing receptor α4β7 integrin by manipulating at the germline level an integrin regulatory domain known as adjacent to metal ion-dependent adhesion site (ADMIDAS). ADMIDAS normally serves to raise the activation threshold of α4β7, thereby stabilizing it in the default nonadhesive state. Lymphocytes from knockin β7 (D146A) mice, which harbor a disrupted ADMIDAS, not only expressed an α4β7 integrin that persistently adhered to mucosal addressin cell adhesion molecule–1 (MAdCAM-1), but also exhibited perturbed cell migration along MAdCAM-1 substrates resulting from improper de-adhesion of the lymphocyte trailing edge. In vivo, aberrantly activated α4β7 enhanced adhesion to Peyer’s patch venules, but suppressed lymphocyte homing to the gut, diminishing the capacity of T cells to induce colitis. Our results underscore the importance of a proper balance in the adhesion and de-adhesion of the α4β7 integrin, both for lymphocyte trafficking to the gut and for colitis progression.

Authors

Eun Jeong Park, J. Rodrigo Mora, Christopher V. Carman, JianFeng Chen, Yoshiteru Sasaki, Guiying Cheng, Ulrich H. von Andrian, Motomu Shimaoka

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Figure 1

Generation of β7 (D146A) mice.

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Generation of β7 (D146A) mice. (A) Targeted insertion to...
(A) Targeted insertion to the Itgb7 locus of the floxed ACN cassette, WT exon 3, and the mutated exon 4 (4*) that contains β7-D146A. The targeting vector, the WT Itgb7 locus, the targeted Itgb7 allele containing floxed ACN cassette, and the mutated Itgb7 (D146A) allele are shown. Exons are shown as filled boxes. Long arm (LA) and short arm (SA) of homology as well as the diphtheria toxin (DT) are also shown. The floxed ACN cassette is deleted in chimeric male mice during spermatogenesis, leaving 1 loxP site. An engineered EcoRI site (E*) was designed to identify the targeted allele by Southern blot analysis. X, XhoI; E, EcoRI; B, BglII; EV, EcoRV. The thick black line indicates the probe used to screen for homologous recombinations. (B) Genotyping and confirmation of deleted ACN cassette by PCR. Genomic DNA isolated from tails was used for PCR analyses. PCR bands are shown for WT (WT/WT, 270 bp), heterozygote (KI/WT, 350 and 270 bp), and homozygote (KI/KI, 350 bp) samples. (C) Sequencing analysis of WT and β7 (D146A) KI mice. DNA sequencing confirmed an aspartate to alanine substitution at position 146 of the mouse β7 integrin gene (boxed regions).