Signaling through FcR?-associated receptors on dendritic cells drives IL-33-dependent TH2-type responses.
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ABSTRACT: Although allergic sensitization can be generated against various allergens, it is unknown how such a diversity of antigens is able to promote TH2-mediated inflammation leading to atopy. Our previous studies demonstrated that allergen-specific IgG immune complexes (ICs) and house dust mite (HDM) extract both induced dendritic cells (DCs) to drive TH2-mediated inflammation, but the mechanism by which these diverse stimuli produce similar responses is unknown.We sought to identify the DC signaling pathways used by TH2 stimuli to promote TH2-mediated inflammation.C57BL/6, Fc?RIII(-/-), FcR?(-/-), and ST2(-/-) mice were sensitized and challenged with HDM, and inflammation was assessed based on results of flow cytometry and histology and cytokine production. Bone marrow-derived DCs from these strains were used in signaling and adoptive transfer experiments.Our findings indicate that 2 distinct TH2 stimuli, ICs and HDM, use the FcR?-associated receptors Fc?RIII and Dectin-2, respectively, to promote TH2-mediated lung inflammation. In this study we demonstrate that both ICs and HDM induce expression of IL-33, a critical mediator in asthma pathogenesis and the differentiation of TH2 cells, in DCs. Upregulation of IL-33 in DCs is dependent on FcR?, Toll-like receptor 4, and phosphoinositide 3-kinase. Exogenous IL-33 is sufficient to restore the development of TH2 responses in FcR?-deficient mice. Finally, adoptive transfer of allergen-pulsed FcR?(+/-) bone-marrow derived DCs restores the development of TH2-type inflammation in FcR?-deficient mice, demonstrating the necessity of this signaling pathway in DCs for allergen-induced inflammation.These data identify a mechanism whereby TH2 stimuli signal through FcR?-associated receptors on DCs to upregulate IL-33 production and induce TH2-mediated allergic airway inflammation.
SUBMITTER: Tjota MY
PROVIDER: S-EPMC4149927 | biostudies-literature | 2014 Sep
REPOSITORIES: biostudies-literature
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