Final published version
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
}
TY - JOUR
T1 - IL-33 causes selective mast cell tolerance to bacterial cell wall products by inducing IRAK1 degradation
AU - Sandig, Hilary
AU - Jobbings, Catherine E
AU - Roldan, Nestor Gonzalez
AU - Whittingham-Dowd, Jayde K
AU - Orinska, Zane
AU - Takeuchi, Osamu
AU - Akira, Shizuo
AU - Bulfone-Paus, Silvia
N1 - © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2013/4
Y1 - 2013/4
N2 - 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.
AB - 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.
KW - Animals
KW - Cells, Cultured
KW - Endotoxins
KW - Immune Tolerance
KW - Interleukin-1 Receptor-Associated Kinases
KW - Interleukin-1 Receptor-Like 1 Protein
KW - Interleukin-33
KW - Interleukins
KW - Lipopolysaccharides
KW - Mast Cells
KW - Mice
KW - Mice, Knockout
KW - Models, Biological
KW - Proteolysis
KW - Receptors, Interleukin
KW - Signal Transduction
U2 - 10.1002/eji.201242786
DO - 10.1002/eji.201242786
M3 - Journal article
C2 - 23404570
VL - 43
SP - 979
EP - 988
JO - European Journal of Immunology
JF - European Journal of Immunology
SN - 0014-2980
IS - 4
ER -