MAdCAM mediates lymphocyte-endothelial cell adhesion in a murine model of chronic colitis

Abstract

Previous studies have revealed that the expression of several endothelial cell adhesion molecules [e.g., intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and mucosal addressin cell adhesion molecule 1 (MAdCAM-1)] is dramatically elevated in the chronically inflamed colonic vasculature of severe combined immunodeficient (SCID) mice reconstituted with congenic CD4+, CD45RB(high) T lymphocytes. The objective of this study was to define the contribution of different endothelial cell adhesion molecules to the lymphocyte-endothelial cell (L/E) adhesion observed in the colonic microvasculature in this experimental model of inflammatory bowel disease. Fluorescently labeled T lymphocytes, isolated from spleens of normal BALB/C mice, were injected intravenously into SCID mice that had been reconstituted with CD4+, CD45RB(high) T lymphocytes either before (3 wk after reconstitution) or after (7 wk postreconstitution) the onset of clinical signs of colitis (i.e., diarrhea, loss of body wt). Intravital fluorescence microscopy was used to quantify L/E adhesion in different-sized venules of the colonic submucosa during the development of colitis. L/E adhesion was noted in some segments of the vasculature in precolitic SCID mice (3 wk after reconstitution) but not in similar-sized vessels of control (wild type and SCID) mice. L/E adhesion was observed in a greater proportion of venules and occurred with greater intensity in the mucosa of colitic mice (7 wk postreconstitution). Pretreatment with a blocking monoclonal antibody against MAdCAM-1, but not ICAM-1 or VCAM-1, significantly and profoundly reduced L/E adhesion in colitic mice. Immunohistochemical staining also revealed the localization of T cells on colonic endothelial cells expressing MAdCAM-1. These findings indicate that MAdCAM-1 is largely responsible for recruiting T lymphocytes into inflamed colonic tissue.

Mechanisms underlying the anti-inflammatory actions of boswellic acid derivatives in experimental colitis

“…Pretreatment with a blocking MAb against MAdCAM-1 significantly and profoundly reduced leukocyte-endothelial adhesion in colitic mice in the CD45RB high -transfer model of colitis and significantly reduces tissue injury (36). Similar protection has been shown using an anti-Eselectin antibody in the cotton-top tamarin model of spontaneous colitis (29).…”

“…An important consequence of endothelial cell activation is an increased expression of glycoproteins that regulate the adhesion of blood cells to the endothelial cell surface and consequently regulate the recruitment of leukocytes into inflamed tissue. ICAM-1, VCAM-1, and MAdCAM-1, as well as E-and P-selectin, are dramatically upregulated on endothelial cells of the colonic vasculature during experimental colitis (4,5,18,22,25,32,36). The importance of these endothelial CAMs in the pathogenesis of intestinal inflammation is evidenced by reports demonstrating reduced disease activity and tissue injury in mice that are genetically deficient in specific adhesion molecules and in wild-type mice treated with blocking antibodies directed against a specific adhesion molecule (25,31,32).…”

The 3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitor Pravastatin Reduces Disease Activity and Inflammation in Dextran-Sulfate Induced Colitis

“…NO blocks leukocyte-endothelial adhesion (Kubes et al, 1991) by preventing the synthesis of endothelial cell adhesion molecules, e.g., MAdCAM-1 (Oshima et al, 2001) VCAM-1, ICAM-1, E-selectin (De Caterina et al, 1995), and P-selectin (Davenpeck et al, 1994). These endothelial adhesion molecules are mobilized in colitis in response to the cytokines found in the gut during active human and animal IBD models (Shigematsu, 1998;Connor et al, 1999;Kawachi et al, 2000a,b,c;Shigematsu et al, 2001). Therefore, therapies to increase NO bioavailability may limit injury in inflammatory conditions at least in part by blocking expression of these adhesive determinants.…”

Increased lymphocyte trafficking to colonic microvessels is dependent on MAdCAM-1 and C-C chemokine mLARC/CCL20 in DSS-induced mice colitis

“…The data are in line with those reported by Shigematsu et al . [8] who described how increased expression of MAdCAM-1, but not of VCAM-1 or intercellular adhesion molecule-1(ICAM-1), mediates the lymphocyte-endothelial cell adhesive interaction in a model of chronic colitis induced by transferring CD45RBhigh T-cells to SCID mice. There are indeed several reports indicating that antibodies against other adhesion molecules (ICAM-1 or VCAM-1) attenuate the increased leucocyte adhesion in intestinal venules [7,18,19].…”

“…We have also demonstrated the functional importance of elevated MAdCAM-1 levels in different animal models of colitis after immunoneutralization of MAdCAM-1 [4,5]. Although other adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) are up-regulated in the intestinal mucosa during inflammatory bowel diseases [3,6,7], the possible involvement of VCAM-1 in lymphocyte recruitment to the inflamed gut is still controversial [4,8]. The relative functional importance of MAdCAM-1 and VCAM-1 in altered lymphocyte trafficking should thus be elucidated.…”