Signaling through FcRγ-associated receptors on dendritic cells drives IL-33–dependent TH2-type responses

• Published in: Journal of allergy and clinical immunology 2014-09, Vol.134 (3), p.706-713.e8
• Main Authors: Tjota, Melissa Y., Hrusch, Cara L., Blaine, Kelly M., Williams, Jesse W., Barrett, Nora A., Sperling, Anne I.
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; allergic airway inflammation; Animals; Antigen-Antibody Complex - immunology; Antigens, Dermatophagoides - immunology; Biological and medical sciences; Cytokines - metabolism; Dendritic cells; Dendritic Cells - immunology; Dermatophagoides pteronyssinus; FcRγ; Fundamental and applied biological sciences. Psychology; Fundamental immunology; house dust mite; Humans; Hypersensitivity - immunology; immune complexes; Immunopathology; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Interleukins - immunology; Lectins, C-Type - metabolism; lungs; Lymphocyte Activation; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, IgG - genetics; Receptors, IgG - metabolism; Receptors, Interleukin - genetics; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Signal Transduction; TH2; Th2 Cells - immunology
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2014.06.013

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, FcγRIII−/−, FcRγ−/−, 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 FcRγ-associated receptors FcγRIII 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 FcRγ, Toll-like receptor 4, and phosphoinositide 3-kinase. Exogenous IL-33 is sufficient to restore the development of TH2 responses in FcRγ-deficient mice. Finally, adoptive transfer of allergen-pulsed FcRγ+/− bone-marrow derived DCs restores the development of TH2-type inflammation in FcRγ-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 FcRγ-associated receptors on DCs to upregulate IL-33 production and induce TH2-mediated allergic airway inflammation.