2010
DOI: 10.1073/pnas.1014669107
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MyD88 signaling in nonhematopoietic cells protects mice against induced colitis by regulating specific EGF receptor ligands

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 My… Show more

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Cited by 134 publications
(139 citation statements)
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“…However, whereas ADAM17 and other metalloproteinases are targets of drug development for inflammatory conditions, ADAM17 deficiency in humans leads to increased intestinal inflammation (47), indicating that this metalloproteinase may also play important roles in gut homeostasis. Importantly, the increased susceptibility of hypomorphic ADAM17 mice to DSS-induced colitis has been directly associated with a loss of ErbB ligand processing and functional EGFR signaling (48,49). Our results show that p40 is involved in activation of ADAM17 in intestinal epithelial cells in vitro and in mice, thus supporting the notion that p40 may play a role in protecting the gastrointestinal tract from acute injury-induced inflammation through ADAM17-mediated production of soluble EGFR ligands.…”
Section: Discussionsupporting
confidence: 74%
“…However, whereas ADAM17 and other metalloproteinases are targets of drug development for inflammatory conditions, ADAM17 deficiency in humans leads to increased intestinal inflammation (47), indicating that this metalloproteinase may also play important roles in gut homeostasis. Importantly, the increased susceptibility of hypomorphic ADAM17 mice to DSS-induced colitis has been directly associated with a loss of ErbB ligand processing and functional EGFR signaling (48,49). Our results show that p40 is involved in activation of ADAM17 in intestinal epithelial cells in vitro and in mice, thus supporting the notion that p40 may play a role in protecting the gastrointestinal tract from acute injury-induced inflammation through ADAM17-mediated production of soluble EGFR ligands.…”
Section: Discussionsupporting
confidence: 74%
“…The exact cellular pathways underlying the homeostatic role of innate recognition in the gut remain to be identified, although increasing evidence suggests such a role for stromal cell types. A homeostatic function in the stroma has been shown for MyD88 (44) and NLRP3 (45). In addition, NLRP6, which also plays a homeostatic role in the gut, is highly expressed in IMFs (46).…”
Section: Discussionmentioning
confidence: 99%
“…IL1R1 −/− mice are protected from colitis development appears at odds with the lack of protection in TRUC.MyD88 −/− mice (4). However, Myd88-mediated TLR signals activate both proinflammatory and antiinflammatory effector mechanisms in a cell type and context-dependent manner (39,40). Presumably, the net result of MyD88 deficiency in TRUC mice is an imbalanced loss of TLR-mediated protective signals resulting in the development of colitis independently of IL-1.…”
Section: Resultsmentioning
confidence: 99%