Journal Article

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

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

2010

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Adaptor Proteins, Vesicular Transport - deficiency / Amphiregulin / Animals / Biological Sciences / Cellular biology / Colitis / Colitis - chemically induced / Colitis - metabolism / Colitis - prevention & control / colon / dextran / Dextran Sulfate / EGF Family of Proteins / Epidermal Growth Factor - metabolism / epidermal growth factor receptors / Epiregulin / Epithelial cells / epithelium / Gene expression / Genetic mutation / Genotype & phenotype / Glycoproteins - metabolism / Hematopoietic System - cytology / Inflammation / Inflammatory bowel disease / Inflammatory bowel diseases / Intercellular Signaling Peptides and Proteins - metabolism / Ligands / lipopolysaccharides / Lipopolysaccharides - pharmacology / Metagenome - drug effects / Mice / Mice, Inbred C57BL / microorganisms / Mutation / Mutation - genetics / Myeloid Differentiation Factor 88 - deficiency / Myeloid Differentiation Factor 88 - metabolism / N-ethyl-N-nitrosourea / Phenotype / Phenotypes / Proteins / Receptor, Epidermal Growth Factor - metabolism / Rodents / signal transduction / Signal Transduction - drug effects / sodium sulfate / Toll like receptors / Toll-Like Receptors - metabolism / Weight loss