CCL25 and CCL28 promote α₄β₇-integrin-dependent adhesion of lymphocytes to MAdCAM-1 under shear flow

Abstract

Inflammatory bowel disease is characterized by the recruitment of lymphocytes to the gut via mucosal vessels. Chemokines are believed to trigger alpha(4)beta(1)- and alpha(4)beta(7)-integrin-mediated adhesion to vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) on mucosal vessels, although the contribution of each pathway and the chemokines involved are not well characterized. These interactions occur under conditions of hemodynamic shear, which is critical in determining how lymphocytes integrate chemokine signals to promote transmigration. To define the role of specific chemokines in mediating lymphocyte adhesion to VCAM-1 and MAdCAM-1, we studied the ability of immobilized chemokines to activate adhesion of human lymphocytes in a flow-based adhesion assay. Adhesion to immobilized MAdCAM-1 was alpha(4)beta(7) dependent, with no contribution from alpha(4)beta(1), whereas alpha(4)beta(1) mediated rolling and static adhesion on VCAM-1. Immobilized CC-chemokine ligand (CCL) 25 and CCL28 were both able to trigger alpha(4)beta(7)-dependent lymphocyte arrest on MAdCAM-1 under shear, highlighting a potential role for these chemokines in the arrest of lymphocytes on postcapillary venules in the gut. Neither had any effect on adhesion to VCAM-1, suggesting that they selectively trigger alpha(4)beta(7)-mediated adhesion. Immobilized CCL21, CCL25, CCL28, and CXC-chemokine ligand (CXCL) 12 all converted rolling adhesion to static arrest on MAdCAM-1 by activating lymphocyte integrins, but only CCL21 and CXCL12 also triggered a motile phenotype characterized by lamelipodia and uropod formation. Thus alpha(4)beta(1)/VCAM-1 and alpha(4)beta(7)/MAdCAM-1 operate independently to support lymphocyte adhesion from flow, and chemokines may act in concert with one chemokine triggering integrin-mediated arrest and a second chemokine promoting motility and transendothelial migration.

Glucocorticoids Suppress CCR9-Mediated Chemotaxis, Calcium Flux, and Adhesion to MAdCAM-1 in Human T Cells

“…However, CCL25 did not stimulate adhesion to VCAM-1 (data not shown). These data are in accord with previous reports of CCL25 stimulated adhesion to MAdCAM-1 without adhesion to VCAM-1, and CXCL12 stimulated adhesion to VCAM-1 or MAdCAM-1, measured in vitro (4,39). DEX treatment reduced CCL25-stimulated cell adhesion to MAdCAM-1 by 60 6 9% (p , 0.05) and increased CXCL12-stimulated adhesion to MAdCAM-1 or VCAM-1 by 113 6 16% (p , 0.001) and 609 6 111% (p , 0.05), respectively (Fig.…”

CCL25 induces α4β7 integrin‐dependent migration of IL‐17+γδ T lymphocytes during an allergic reaction

“…Indeed, selective blocking mAbs against α 4 β 1 integrin inhibited human γδ T-lymphocyte adhesion to cytokine-activated endothelial cells [24]. Moreover, CCL25 has been shown to induce T lymphocyte adhesion via the interaction of α 4 β 7 and α 4 β 1 integrins to MadCAM-1 and VCAM-1, respectively [16,17]. These data corroborate our findings that CCL25 induced the transmigration of γδ T lymphocytes through endothelial cells, via the interaction of α 4 β 7 integrin to MadCAM-1/VCAM-1.…”

T-cell recruitment to the intestinal mucosa

“…Moreover, the interaction of adoptively transferred LPLs and IELs with small intestinal vascular endothelium is partially inhibited in vivo with anti-CCL25 antibody or by CCR9 desensitization [23]. A probable function for CCL25 in this setting is to promote a 4 b 7 integrin-dependent adhesion of CCR9 + T cells to MadCAM-1 [24]. Because in the experiments described above [18,23], recipient mice only received T cells, the presence of antigen or additional inflammatory signals is clearly not needed for circulating CCR9 + a 4 b 7 + T cells to gain entry into the intestinal LP and epithelium.…”