PMID- 21041656 OWN - NLM STAT- MEDLINE DCOM- 20101221 LR - 20211020 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 107 IP - 46 DP - 2010 Nov 16 TI - MyD88 signaling in nonhematopoietic cells protects mice against induced colitis by regulating specific EGF receptor ligands. PG - 19967-72 LID - 10.1073/pnas.1014669107 [doi] AB - 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. FAU - Brandl, Katharina AU - Brandl K AD - Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA. FAU - Sun, Lei AU - Sun L FAU - Neppl, Christina AU - Neppl C FAU - Siggs, Owen M AU - Siggs OM FAU - Le Gall, Sylvain M AU - Le Gall SM FAU - Tomisato, Wataru AU - Tomisato W FAU - Li, Xiaohong AU - Li X FAU - Du, Xin AU - Du X FAU - Maennel, Daniela N AU - Maennel DN FAU - Blobel, Carl P AU - Blobel CP FAU - Beutler, Bruce AU - Beutler B LA - eng GR - HHSN272200700038C/AI/NIAID NIH HHS/United States GR - R01 GM064750/GM/NIGMS NIH HHS/United States GR - R37 GM067759/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20101101 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Adaptor Proteins, Vesicular Transport) RN - 0 (Amphiregulin) RN - 0 (Areg protein, mouse) RN - 0 (EGF Family of Proteins) RN - 0 (Epiregulin) RN - 0 (Ereg protein, mouse) RN - 0 (Glycoproteins) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (Ligands) RN - 0 (Lipopolysaccharides) RN - 0 (Myeloid Differentiation Factor 88) RN - 0 (TICAM-1 protein, mouse) RN - 0 (Toll-Like Receptors) RN - 62229-50-9 (Epidermal Growth Factor) RN - 9042-14-2 (Dextran Sulfate) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Adaptor Proteins, Vesicular Transport/deficiency MH - Amphiregulin MH - Animals MH - Colitis/chemically induced/metabolism/*prevention & control MH - Dextran Sulfate MH - EGF Family of Proteins MH - Epidermal Growth Factor/*metabolism MH - Epiregulin MH - ErbB Receptors/*metabolism MH - Glycoproteins/*metabolism MH - Hematopoietic System/*cytology MH - Intercellular Signaling Peptides and Proteins/*metabolism MH - Ligands MH - Lipopolysaccharides/pharmacology MH - Metagenome/drug effects MH - Mice MH - Mice, Inbred C57BL MH - Mutation/genetics MH - Myeloid Differentiation Factor 88/deficiency/*metabolism MH - Phenotype MH - *Signal Transduction/drug effects MH - Toll-Like Receptors/metabolism PMC - PMC2993336 COIS- The authors declare no conflict of interest. EDAT- 2010/11/03 06:00 MHDA- 2010/12/22 06:00 PMCR- 2011/05/16 CRDT- 2010/11/03 06:00 PHST- 2010/11/03 06:00 [entrez] PHST- 2010/11/03 06:00 [pubmed] PHST- 2010/12/22 06:00 [medline] PHST- 2011/05/16 00:00 [pmc-release] AID - 1014669107 [pii] AID - 201014669 [pii] AID - 10.1073/pnas.1014669107 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2010 Nov 16;107(46):19967-72. doi: 10.1073/pnas.1014669107. Epub 2010 Nov 1.