title: IL-33 causes selective mast cell tolerance to bacterial cell wall products by inducing IRAK1 degradation.
abstract: Mast cells are important cellular constituents of epithelial-mesenchymal interactions, densely located at sites of microbial entry into the host where they are continuously exposed to products from commensals. In order to avoid excessive activation and the associated pathology, mast cell responses to TLR agonists must be tightly regulated. Here, we show that exposure in vitro to subactivating levels of the epithelial cell product, IL-33, renders mast cells insensitive to bacterial cell wall products. Mast cell responsiveness to Ag, cytoplasmic dsDNA, and TLR7/8 agonists is unaffected or enhanced by IL-33. The IL-33-induced mast cell selective tolerance requires the IL-33 receptor ST2 and peritoneal mast cells from St2(-/-) mice display a constitutively activated phenotype, demonstrated by increased expression of activation markers including CD11b and CD28. IL-33 exposure neither affects the levels of TLR4, MyD88, TIRAP, IL-1R associated kinase 2 (IRAK2), or IRAK4, nor induces persistent A20 or Tollip expression, but potently causes ST2-dependent IRAK1 degradation. We show that while IRAK2 is redundant for TLR4 signaling, IRAK1 is essential for TLR4 signaling in mast cells. We suggest that IL-33 produced during homeostasis retains mast cells in an unresponsive state to bacterial cell wall products via IRAK1 degradation, thus preventing chronic inflammation and tissue destruction.
authors: Faculty of Human and Medical Sciences, University of Manchester, Manchester, UK.
authors: Hilary
authors: H
authors: Sandig
authors: Catherine E
authors: CE
authors: Jobbings
authors: Nestor Gonzalez
authors: NG
authors: Roldan
authors: Jayde K
authors: JK
authors: Whittingham-Dowd
authors: Zane
authors: Z
authors: Orinska
authors: Osamu
authors: O
authors: Takeuchi
authors: Shizuo
authors: S
authors: Akira
authors: Silvia
authors: S
authors: Bulfone-Paus
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004731:Endotoxins / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects* / Q000235:genetics; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000276:immunology*; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D059748:Proteolysis; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D004731:Endotoxins; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D008070:Lipopolysaccharides; D018123:Receptors, Interleukin; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse