Matrix metalloproteinase 13 modulates intestinal epithelial barrier integrity in inflammatory diseases by activating TNF

Authors

  • Roosmarijn E. Vandenbroucke,

    1. Department for Molecular Biomedical Research, VIB, Ghent, Belgium
    2. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
    Search for more papers by this author
  • Eline Dejonckheere,

    1. Department for Molecular Biomedical Research, VIB, Ghent, Belgium
    2. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
    Search for more papers by this author
  • Filip Van Hauwermeiren,

    1. Department for Molecular Biomedical Research, VIB, Ghent, Belgium
    2. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
    Search for more papers by this author
  • Sofie Lodens,

    1. Department for Molecular Biomedical Research, VIB, Ghent, Belgium
    2. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
    Search for more papers by this author
  • Riet De Rycke,

    1. Department for Molecular Biomedical Research, VIB, Ghent, Belgium
    2. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
    Search for more papers by this author
  • Elien Van Wonterghem,

    1. Department for Molecular Biomedical Research, VIB, Ghent, Belgium
    2. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
    Search for more papers by this author
  • An Staes,

    1. Department of Medical Protein Research, VIB, Ghent, Belgium
    2. Department of Biochemistry, Ghent University, Ghent, Belgium
    Search for more papers by this author
  • Kris Gevaert,

    1. Department of Medical Protein Research, VIB, Ghent, Belgium
    2. Department of Biochemistry, Ghent University, Ghent, Belgium
    Search for more papers by this author
  • Carlos López-Otin,

    1. Departamento de Bioquimica y Biologia Molecular, Instituto Universitario de Oncologia, Universidad de Oviedo, Oviedo, Spain
    Search for more papers by this author
  • Claude Libert

    Corresponding author
    1. Department for Molecular Biomedical Research, VIB, Ghent, Belgium
    2. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
    Search for more papers by this author

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.

Ancillary