IL-33-dependent induction of allergic lung inflammation by FcγRIII signaling

J Clin Invest. 2013 May;123(5):2287-97. doi: 10.1172/JCI63802. Epub 2013 Apr 15.


Atopic asthma is a chronic inflammatory disease of the lungs generally marked by excessive Th2 inflammation. The role of allergen-specific IgG in asthma is still controversial; however, a receptor of IgG-immune complexes (IgG-ICs), FcγRIII, has been shown to promote Th2 responses through an unknown mechanism. Herein, we demonstrate that allergen-specific IgG-ICs, formed upon reexposure to allergen, promoted Th2 responses in two different models of IC-mediated inflammation that were independent of a preformed T cell memory response. Development of Th2-type airway inflammation was shown to be both FcγRIII and TLR4 dependent, and T cells were necessary and sufficient for this process to occur, even in the absence of type 2 innate lymphoid cells. We sought to identify downstream targets of FcγRIII signaling that could contribute to this process and demonstrated that bone marrow-derived DCs, alveolar macrophages, and respiratory DCs significantly upregulated IL-33 when activated through FcγRIII and TLR4. Importantly, IC-induced Th2 inflammation was dependent on the ST2/IL-33 pathway. Our results suggest that allergen-specific IgG can enhance secondary responses by ligating FcγRIII on antigen-presenting cells to augment development of Th2-mediated responses in the lungs via an IL-33-dependent mechanism.

Publication types

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

MeSH terms

  • Animals
  • Asthma / metabolism
  • Bone Marrow Cells / cytology
  • Dendritic Cells / cytology
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Hypersensitivity
  • Hypersensitivity, Immediate / metabolism
  • Immunoglobulin G / metabolism
  • Inflammation / metabolism*
  • Interleukin-33
  • Interleukins / metabolism*
  • Leukocytes, Mononuclear / cytology
  • Lung / pathology*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Receptors, IgG / metabolism*
  • Signal Transduction
  • Th2 Cells


  • Il33 protein, mouse
  • Immunoglobulin G
  • Interleukin-33
  • Interleukins
  • Receptors, IgG