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MyD88 signaling in nonhematopoietic cells protects mice against induced colitis by regulating specific EGF receptor ligands.

Toll-like receptors (TLRs) trigger intestinal inflammation when the epithelial barrier is breached by physical trauma or pathogenic microbes. Although it has been shown that TLR-mediated signals are ultimately protective in models of acute intestinal inflammation [such as dextran sulfate sodium (DSS)-induced colitis], it is less clear which cells mediate protection. Here we demonstrate that TLR signaling in the nonhematopoietic compartment confers protection in acute DSS-induced colitis. Epithelial cells of MyD88/Trif-deficient mice express diminished levels of the epidermal growth factor receptor (EGFR) ligands amphiregulin (AREG) and epiregulin (EREG), and systemic lipopolysaccharide administration induces their expression in the colon. N-ethyl-N-nitrosourea (ENU)-induced mutations in Adam17 (which is required for AREG and EREG processing) and in Egfr both produce a strong DSS colitis phenotype, and the Adam17 mutation exerts its deleterious effect in the nonhematopoietic compartment. The effect of abrogation of TLR signaling is mitigated by systemic administration of AREG. A TLR→MyD88→AREG/EREG→EGFR signaling pathway is represented in nonhematopoietic cells of the intestinal tract, responds to microbial stimuli once barriers are breached, and mediates protection against DSS-induced colitis.

Pubmed ID: 21041656

Authors

  • Brandl K
  • Sun L
  • Neppl C
  • Siggs OM
  • Le Gall SM
  • Tomisato W
  • Li X
  • Du X
  • Maennel DN
  • Blobel CP
  • Beutler B

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

November 16, 2010

Associated Grants

  • Agency: PHS HHS, Id: HHSN272200700038C
  • Agency: NIGMS NIH HHS, Id: R37 GM067759

Mesh Terms

  • Adaptor Proteins, Vesicular Transport
  • Amphiregulin
  • Animals
  • Colitis
  • Dextran Sulfate
  • EGF Family of Proteins
  • Epidermal Growth Factor
  • Epiregulin
  • Glycoproteins
  • Hematopoietic System
  • Intercellular Signaling Peptides and Proteins
  • Ligands
  • Lipopolysaccharides
  • Metagenome
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Myeloid Differentiation Factor 88
  • Phenotype
  • Receptor, Epidermal Growth Factor
  • Signal Transduction
  • Toll-Like Receptors