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Blocking MAdCAM-1 in vivo reduces leukocyte extravasation and reverses chronic inflammation in experimental colitis

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Abstract

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.

Conclusion

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.

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Abbreviations

DSS:

Dextran sodium sulphate

MAdCAM-1:

Mucosal addressin cell adhesion molecule

TNF-α:

Tumour necrosis factor α

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Acknowledgements

This work was supported by a grant from the Deutsche Forschungsgemeinschaft (AN334/1-1) to M. Anthuber and S. Farkas, and by the Bundesministerium für Bildung und Forschung (BMBF) to S. Farkas. The authors thank Florian Obermeier for scoring the histologic slices.

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Correspondence to Stefan Farkas.

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S. Farkas and M. Hornung contributed equally to this work.

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Farkas, S., Hornung, M., Sattler, C. et al. Blocking MAdCAM-1 in vivo reduces leukocyte extravasation and reverses chronic inflammation in experimental colitis. Int J Colorectal Dis 21, 71–78 (2006). https://doi.org/10.1007/s00384-004-0709-y

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