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

Katharina Brandl, Lei Sun, Christina Neppl, Owen M. Siggs, Sylvain M. Le Gall, Wataru Tomisato, Xiaohong Li, Xin Du, Daniela N. Maennel, Carl P. Blobel, Bruce Beutler

Research output: Contribution to journalArticle

114 Scopus citations

Abstract

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. W-ethyl-W-nitrosourea (ENU)-induced mutations in Adam17 (which is required for AREG and EREG processing) and in Egfrboth 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/ERE- G→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.

Original languageEnglish (US)
Pages (from-to)19967-19972
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number46
DOIs
StatePublished - Nov 16 2010

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Keywords

  • ENU mutagenesis
  • Epidermal growth factor receptor signaling
  • Inflammatory bowel disease
  • Intestinal homeostasis
  • Toll-like receptor signaling

ASJC Scopus subject areas

  • General

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