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

J Allergy Clin Immunol. 2014 Sep;134(3):706-713.e8. doi: 10.1016/j.jaci.2014.06.013. Epub 2014 Jul 31.


Background: 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.

Objective: We sought to identify the DC signaling pathways used by TH2 stimuli to promote TH2-mediated inflammation.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Dendritic cells; FcRγ; T(H)2; allergic airway inflammation; house dust mite; immune complexes; lungs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigen-Antibody Complex / immunology
  • Antigens, Dermatophagoides / immunology
  • Cytokines / metabolism
  • Dendritic Cells / immunology*
  • Humans
  • Hypersensitivity / immunology*
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Interleukins / immunology
  • Lectins, C-Type / metabolism*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, IgG / genetics
  • Receptors, IgG / metabolism*
  • Receptors, Interleukin / genetics
  • Signal Transduction
  • Th2 Cells / immunology*


  • Antigen-Antibody Complex
  • Antigens, Dermatophagoides
  • Cytokines
  • Il1rl1 protein, mouse
  • Il33 protein, mouse
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Interleukins
  • Lectins, C-Type
  • Receptors, IgG
  • Receptors, Interleukin
  • dectin-2, mouse