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

K Brandl, L Sun, C Neppl, OM Siggs… - Proceedings of the …, 2010 - National Acad Sciences
K Brandl, L Sun, C Neppl, OM Siggs, SM Le Gall, W Tomisato, X Li, X Du, DN Maennel…
Proceedings of the National Academy of Sciences, 2010National Acad Sciences
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 …
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.
National Acad Sciences