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Published on: April 21, 2015
Blocking MAdCAM-1 in vivo reduces leukocyte extravasation and reverses chronic inflammation in experimental colitis
Stefan Farkas1, Matthias Hornung, Christine Sattler
1Department of Surgery, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany. stefan.farkas@klinik.uni-regensburg.de
Insights
Targeting mucosal addressin cell adhesion molecule-1 (MAdCAM-1) significantly reduced leukocyte adhesion and intestinal inflammation in a mouse model of chronic colitis. This highlights MAdCAM-1 as a potential therapeutic target for inflammatory bowel diseases.
Area of Science:
- Gastroenterology
- Immunology
- Cell Biology
Background:
- Leukocyte recruitment is vital for intestinal inflammation.
- Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) mediates these interactions in the gut.
- The role of MAdCAM-1 in the intestinal microcirculation requires further investigation.
Purpose of the Study:
- To investigate the pathophysiologic role of MAdCAM-1 in the intestinal microcirculation in vivo.
- To assess the therapeutic potential of targeting MAdCAM-1 in experimental colitis.
Main Methods:
- Chronic colitis was induced using dextran sodium sulfate (DSS) in a mouse model.
- MAdCAM-1 expression was quantified using immunohistochemistry, Western blotting, and real-time PCR.
- Intravital microscopy evaluated leukocyte-endothelium interactions and extravasation, with and without anti-MAdCAM-1 treatment.
Main Results:
- MAdCAM-1 expression was significantly upregulated in mice with DSS-induced chronic colitis at both protein and mRNA levels.
- Anti-MAdCAM-1 treatment reduced leukocyte sticking and extravasation by over 60%.
- Intestinal inflammation, assessed by histologic grading score, was reduced by 45% following anti-MAdCAM-1 therapy.
Conclusions:
- MAdCAM-1 plays a distinct role in inflammatory intestinal diseases.
- Therapeutic strategies targeting MAdCAM-1 show promise for treating chronic colitis.
- In vivo data support MAdCAM-1 as a viable therapeutic target for inflammatory bowel conditions.
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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