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

Overview

MeSH Major

  • Colitis
  • Epidermal Growth Factor
  • Glycoproteins
  • Hematopoietic System
  • Intercellular Signaling Peptides and Proteins
  • Myeloid Differentiation Factor 88
  • Receptor, Epidermal Growth Factor
  • Signal Transduction

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. 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.

publication date

  • November 16, 2010

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2993336

Digital Object Identifier (DOI)

  • 10.1073/pnas.1014669107

PubMed ID

  • 21041656

Additional Document Info

start page

  • 19967

end page

  • 72

volume

  • 107

number

  • 46