Critical role of the disintegrin metalloprotease ADAM17 for intestinal inflammation and regeneration in mice

The protease a disintegrin and metalloprotease (ADAM) 17 cleaves tumor necrosis factor (TNF), L-selectin, and epidermal growth factor receptor (EGF-R) ligands from the plasma membrane. ADAM17 is expressed in most tissues and is up-regulated during inflammation and cancer. ADAM17-deficient mice are n...

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Bibliographic Details
Published in:The Journal of experimental medicine 2010-08, Vol.207 (8), p.1617-1624
Main Authors: Chalaris, Athena, Adam, Nina, Sina, Christian, Rosenstiel, Philip, Lehmann-Koch, Judith, Schirmacher, Peter, Hartmann, Dieter, Cichy, Joanna, Gavrilova, Olga, Schreiber, Stefan, Jostock, Thomas, Matthews, Vance, Häsler, Robert, Becker, Christoph, Neurath, Markus F, Reiss, Karina, Saftig, Paul, Scheller, Jürgen, Rose-John, Stefan
Format: Article
Language:English
Subjects:
ADAM Proteins - deficiency
ADAM Proteins - genetics
ADAM Proteins - metabolism
ADAM17 Protein
Animal Structures - abnormalities
Animal Structures - metabolism
Animals
Brain - metabolism
Brief Definitive Report
Cell Proliferation - drug effects
Chemokines - metabolism
Colon - metabolism
Colon - pathology
Cyclin D1 - metabolism
Cytokines - metabolism
Dextran Sulfate - pharmacology
Epithelial Cells - cytology
Epithelial Cells - drug effects
Epithelial Cells - metabolism
Female
Gene Expression - genetics
Gene Expression Profiling
Inflammatory Bowel Diseases - chemically induced
Inflammatory Bowel Diseases - enzymology
Inflammatory Bowel Diseases - immunology
Inflammatory Bowel Diseases - pathology
Intestinal Mucosa - enzymology
Intestinal Mucosa - immunology
Intestinal Mucosa - pathology
Intestinal Mucosa - physiology
L-Selectin - metabolism
Liver - metabolism
Mammary Glands, Animal - growth & development
Mice
Mice, Inbred C57BL
Mice, Transgenic
Permeability
Peroxidase - metabolism
Phosphorylation - drug effects
Receptors, Tumor Necrosis Factor, Type II - blood
Regeneration
STAT3 Transcription Factor - metabolism
Transforming Growth Factor alpha - metabolism
Transforming Growth Factor alpha - pharmacology
Tumor Necrosis Factor-alpha - metabolism
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Summary:The protease a disintegrin and metalloprotease (ADAM) 17 cleaves tumor necrosis factor (TNF), L-selectin, and epidermal growth factor receptor (EGF-R) ligands from the plasma membrane. ADAM17 is expressed in most tissues and is up-regulated during inflammation and cancer. ADAM17-deficient mice are not viable. Conditional ADAM17 knockout models demonstrated proinflammatory activities of ADAM17 in septic shock via shedding of TNF. We used a novel gene targeting strategy to generate mice with dramatically reduced ADAM17 levels in all tissues. The resulting mice called ADAM17(ex/ex) were viable, showed compromised shedding of ADAM17 substrates from the cell surface, and developed eye, heart, and skin defects as a consequence of impaired EGF-R signaling caused by failure of shedding of EGF-R ligands. Unexpectedly, although the intestine of unchallenged homozygous ADAM17(ex/ex) mice was normal, ADAM17(ex/ex) mice showed substantially increased susceptibility to inflammation in dextran sulfate sodium colitis. This was a result of impaired shedding of EGF-R ligands resulting in failure to phosphorylate STAT3 via the EGF-R and, consequently, in defective regeneration of epithelial cells and breakdown of the intestinal barrier. Besides regulating the systemic availability of the proinflammatory cytokine TNF, our results demonstrate that ADAM17 is needed for vital regenerative activities during the immune response. Thus, our mouse model will help investigate ADAM17 as a potential drug target.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20092366