β7-Integrin exacerbates experimental DSS-induced colitis in mice by directing inflammatory monocytes into the colon.
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 gene-2 (RAG-2)-deficient mice from dextran sodium sulfate (DSS)-induced colitis and coincides with decreased numbers of colonic effector monocytes. We also show that β7-integrin is expressed on most CD11b(+)CD64(low)Ly6C(+) bone marrow progenitors and contributes to colonic recruitment of these proinflammatory monocytes. Importantly, adoptive transfer of CD115(+) wild-type (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 by directing inflammatory monocytes into the colon.
Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany.
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A
Schippers
Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany.
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M
Muschaweck
Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany.
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T
Clahsen
Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany.
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S
Tautorat
Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany.
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L
Grieb
Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany.
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K
Tenbrock
Institute of Pathology, Klinikum Braunschweig, Braunschweig, Germany.
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N
Gaßler
Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany.
N
N
Wagner
D019264:Adoptive Transfer; D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D002465:Cell Movement; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000473:pathology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D016264:Dextran Sulfate; D018450:Disease Progression; D004198:Disease Susceptibility; D005260:Female; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D039641:Integrin beta Chains / Q000235:genetics / Q000276:immunology*; D016023:Integrins / Q000235:genetics / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D009088:Mucoproteins; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction
D000950:Antigens, Ly; D039481:CD11b Antigen; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D039641:Integrin beta Chains; D016023:Integrins; C494192:Ly-6C antigen, mouse; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; C499308:Rag2 protein, mouse; D017452:Receptors, IgG; C071777:integrin alpha4beta7; C091368:integrin beta7; D016264:Dextran Sulfate