ICAM-1-dependent pathways regulate colonic eosinophilic inflammation (original) (raw)

2006, Journal of Leukocyte Biology

Eosinophilic inflammation is a common feature of numerous eosinophil-associated gastrointestinal (GI) diseases. Central to eosinophil migration into the GI tract are the integrin-mediated interactions with adhesion molecules. Although the mechanisms regulating eosinophil homing into the small intestine have begun to be elucidated, the adhesion pathways responsible for eosinophil trafficking into the large intestine are unknown. We investigated the role of adhesion pathways in eosinophil recruitment into the large intestine during homeostasis and disease. First, using a hapten-induced colonic injury model, we demonstrate that in contrast to the small intestine, eosinophil recruitment into the colon is regulated by a ␣ 4 ␤ 7 /mucosal addressin cell adhesion molecule-1-independent pathway. Characterization of integrin expression on eosinophils by flow cytometry analysis revealed that colonic CC chemokine receptor 3 ؉ eosinophils express the intercellular adhesion molecule-1 (ICAM-1) counter-receptor integrins ␣ L , ␣ M , and ␤ 2 . Using ICAM-1-deficient mice and anti-ICAM-1 neutralizing antibodies, we show that hapten-induced colonic eosinophilic inflammation is critically dependent on ICAM-1. These studies demonstrate that ␤ 2 -integrin/ICAM-1-dependent pathways are integral to eosinophil recruitment into the colon during GI inflammation associated with colonic injury. J. Leukoc. Biol. 80: 000 -000; 2006. chemokine and cytokine signaling, eosinophil adhesion molecules (e.g., selectins and integrins), and integrin receptors [e.g., vascular cell adhesion molecule-1 (VCAM-1), mucosal addressin cell adhesion molecule-1 (MAdCAM-1), and intercellular adhesion molecule 1 (ICAM-1)] expressed on vascular endothelial cells . Integrins are heterodimeric surface molecules consisting of an ␣and ␤-chain, and eosinophils express members of the ␤ 1 (␣ 4 ␤ 1 and ␣ 6 ␤ 1 )-, ␤ 2 (␣ L ␤ 2 , ␣ M ␤ 2 , ␣ X ␤ 2 , and ␣ D ␤ 2 )-, and ␤ 7 (␣ 4 ␤ 7 )-integrin families [18 -22]. These various integrin molecules interact selectively with adhesion receptors (VCAM-1, MAdCAM-1, ICAM-1, -2, and -3, and fibrinogen) expressed on the vascular endothelium. ␣ 4 ␤ 1 selectively binds to VCAM-1 and fibronectin, and ␣ 6 ␤ 1 is the primary ligand for the extracellular matrix protein laminin. The ␣ 4 ␤ 7 -integrin selectively binds to MAdCAM-1, and lymophocyte function-associated antigen-1 (LFA-1; ␣ L ␤ 2 ) and membrane-activated complex-1 (MAC-1; ␣ M ␤ 2 ) bind to ICAM-1. In addition, LFA-1 (␣ L ␤ 2 ) can bind ICAM-2 and -3, and ␣ D ␤ 2 has been shown to bind VCAM-1 and ICAM-3. Leukocyte integrin/intercellular adhesion molecule interactions, particularly LFA-1/ICAM-1 and very late antigen (VLA)-4/VCAM-1, are regulated by cytokines and chemokines such as IL-1 (␣ and ␤), tumor necrosis fator (TNF; ␣ and ␤), IL-4, and IL-13 [23]. IL-1 and TNF stimulate VCAM-1 and ICAM-1 expression on a variety of cell types. By contrast, IL-4 and IL-13 differentially enhance the expression of VCAM-1, having little impact on ICAM-1. Chemokines alter the activation state and selectivity of adhesion molecules . For example, treatment of eosinophils with MCP-3, RANTES, or eotaxin-2 switches eosinophils from a ␤ 1 -integrin/VCAM-1-dominant to a ␤ 2 -integrin/ICAM-1-dominant, interacting cell .