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.
Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA.
Katharina
K
Brandl
Lei
L
Sun
Christina
C
Neppl
Owen M
OM
Siggs
Sylvain M
SM
Le Gall
Wataru
W
Tomisato
Xiaohong
X
Li
Xin
X
Du
Daniela N
DN
Maennel
Carl P
CP
Blobel
Bruce
B
Beutler
D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency; D066258:Amphiregulin; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D016264:Dextran Sulfate; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066260:Epiregulin; D066246:ErbB Receptors / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism*; D006413:Hematopoietic System / Q000166:cytology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D054892:Metagenome / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D066258:Amphiregulin; D016264:Dextran Sulfate; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor; D066260:Epiregulin; D066246:ErbB Receptors; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; C587849:Areg protein, mouse; C587881:Ereg protein, mouse; C476286:Ticam1 protein, mouse