title: Matrix metalloproteinase 13 modulates intestinal epithelial barrier integrity in inflammatory diseases by activating TNF.
abstract: Several pathological processes, such as sepsis and inflammatory bowel disease (IBD), are associated with impairment of intestinal epithelial barrier. Here, we investigated the role of matrix metalloproteinase MMP13 in these diseases. We observed that MMP13(-/-) mice display a strong protection in LPS- and caecal ligation and puncture-induced sepsis. We could attribute this protection to reduced LPS-induced goblet cell depletion, endoplasmic reticulum stress, permeability and tight junction destabilization in the gut of MMP13(-/-) mice compared to MMP13(+/+) mice. Both in vitro and in vivo, we found that MMP13 is able to cleave pro-TNF into bioactive TNF. By LC-MS/MS, we identified three MMP13 cleavage sites, which proves that MMP13 is an alternative TNF sheddase next to the TNF converting enzyme TACE. Similarly, we found that the same mechanism was responsible for the observed protection of the MMP13(-/-) mice in a mouse model of DSS-induced colitis. We identified MMP13 as an important mediator in sepsis and IBD via the shedding of TNF. Hence, we propose MMP13 as a novel drug target for diseases in which damage to the gut is essential.
authors.affiliation: Department for Molecular Biomedical Research, VIB, Ghent, Belgium.
authors.forename: Roosmarijn E
authors.initials: RE
authors.lastname: Vandenbroucke
authors.forename: Eline
authors.initials: E
authors.lastname: Dejonckheere
authors.forename: Filip
authors.initials: F
authors.lastname: Van Hauwermeiren
authors.forename: Sofie
authors.initials: S
authors.lastname: Lodens
authors.forename: Riet
authors.initials: R
authors.lastname: De Rycke
authors.forename: Elien
authors.initials: E
authors.lastname: Van Wonterghem
authors.forename: An
authors.initials: A
authors.lastname: Staes
authors.forename: Kris
authors.initials: K
authors.lastname: Gevaert
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otin
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016264:Dextran Sulfate; D059865:Endoplasmic Reticulum Stress; D005260:Female; D017353:Gene Deletion; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008070:Lipopolysaccharides; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010539:Permeability; D018805:Sepsis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D019108:Tight Junctions / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate; D053509:Matrix Metalloproteinase 13
keywords: IBD; intestinal permeability; matrix metalloproteinase; sepsis; tumour necrosis factor