Blocking MAdCAM-1 in vivo reduces leukocyte extravasation and reverses chronic inflammation in experimental colitis.
BACKGROUND
Leukocyte recruitment to sites of intestinal inflammation is a crucial multi-step process, leading ultimately to the accumulation of cells in the inflamed tissue. These interactions in the gut are critically dependent on the mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is expressed on endothelial cells within the mesenteric lymph nodes and the lamina propria of the intestine. Here, we investigate the pathophysiologic role of MAdCAM-1 in the intestinal microcirculation in vivo.


METHODS
Using a standard mouse model, chronic colitis was established after four cycles of dextran sodium sulfate (DSS) application. MAdCAM-1 expression was investigated by immunohistochemistry and Western blotting, as well as real-time polymerase chain reaction (PCR). Intravital microscopy was used to study the role of MAdCAM-1 on leukocyte-endothelium interactions and leukocyte extravasation.


RESULTS
Significant changes in MAdCAM-1 were observed in mice with chronic DSS-induced colitis. Upregulation of MAdCAM-1 expression in chronic colitis was demonstrated on a protein and messenger ribonucleic acid (mRNA) level. Anti-MAdCAM-1 treatment lead to a marked reduction (>60%) of leukocyte sticking and extravasation in vivo, compared to the controls. This was parallelled by a significant reduction (45%) of intestinal inflammation, as measured by the histologic grading score.


CONCLUSIONS
These in vivo results demonstrate a distinct role of MAdCAM-1 in inflammatory intestinal diseases, and suggest that therapeutic strategies targeting this adhesion molecule could be useful in the treatment of chronic colitis.
Farkas
Stefan
S
Department of Surgery, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany. stefan.farkas@klinik.uni-regensburg.de
Hornung
Matthias
M
Sattler
Christine
C
Edtinger
Karoline
K
Steinbauer
Markus
M
Anthuber
Matthias
M
Schlitt
Hans J
HJ
Herfarth
Hans
H
Geissler
Edward K
EK
D000818:Animals; D000974:Antibodies, Antinuclear / Q000494:pharmacology*; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D003092:Colitis / Q000378:metabolism / Q000473:pathology*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000276:immunology; D005260:Female; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000032:analysis; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000378:metabolism*; D007962:Leukocytes; D051379:Mice; D008807:Mice, Inbred BALB C; D009088:Mucoproteins; D016133:Polymerase Chain Reaction / Q000379:methods; D011336:Probability; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric
D000974:Antibodies, Antinuclear; D015815:Cell Adhesion Molecules; D018836:Inflammation Mediators; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D018799:Intercellular Adhesion Molecule-1; D016264:Dextran Sulfate