Thursday, July 16, 2015
Grand Hall and Gallery, Ground Floor & 1st Floor (Maritim Hotel)
Leukocyte recruitment is pivotal for the initiation and perpetuation of inflammatory bowel disease (IBD) and controlled by the specificity and interactions of chemokines and adhesion molecules. Interactions of the adhesion molecules α4β7 integrin and mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) promote the accumulation of pathogenic T cell populations in the inflamed intestine.
We aimed to elucidate the significance of β7 integrin expression on innate immune cells for the pathogenesis of IBD. We demonstrate that β7 integrin-deficiency protects recombination activating genes (RAG-2)-deficient mice from dextran sodium sulphate (DSS)-induced colitis and coincides with decreased numbers of colonic effector monocytes. We also show that β7 integrin is expressed on most CD11b+CD64lowLy6C+ bone marrow progenitors and contributes to colonic recruitment of these pro-inflammatory monocytes. Importantly, adoptive transfer of CD115+ WT monocytes partially restored the susceptibility of RAG-2/β7 integrin double-deficient mice to DSS-induced colitis, thereby demonstrating the functional importance of β7 integrin-expressing monocytes for the development of DSS colitis. We also reveal that genetic ablation of MAdCAM-1 ameliorates experimental colitis in RAG-2-deficient mice as well. In summary, we demonstrate a previously unknown role of α4β7 integrin/MAdCAM-1 interactions as drivers of colitis through directing of inflammatory monocytes into the colon.
(Supported by DFG Grant DFG/WA 1127/2-2)
We aimed to elucidate the significance of β7 integrin expression on innate immune cells for the pathogenesis of IBD. We demonstrate that β7 integrin-deficiency protects recombination activating genes (RAG-2)-deficient mice from dextran sodium sulphate (DSS)-induced colitis and coincides with decreased numbers of colonic effector monocytes. We also show that β7 integrin is expressed on most CD11b+CD64lowLy6C+ bone marrow progenitors and contributes to colonic recruitment of these pro-inflammatory monocytes. Importantly, adoptive transfer of CD115+ WT monocytes partially restored the susceptibility of RAG-2/β7 integrin double-deficient mice to DSS-induced colitis, thereby demonstrating the functional importance of β7 integrin-expressing monocytes for the development of DSS colitis. We also reveal that genetic ablation of MAdCAM-1 ameliorates experimental colitis in RAG-2-deficient mice as well. In summary, we demonstrate a previously unknown role of α4β7 integrin/MAdCAM-1 interactions as drivers of colitis through directing of inflammatory monocytes into the colon.
(Supported by DFG Grant DFG/WA 1127/2-2)