IL-33–dependent induction of allergic lung inflammation by FcγRIII signaling
Melissa Y. Tjota, … , Paul J. Bryce, Anne I. Sperling
Melissa Y. Tjota, … , Paul J. Bryce, Anne I. Sperling
Published April 15, 2013
Citation Information: J Clin Invest. 2013;123(5):2287-2297. https://doi.org/10.1172/JCI63802.
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Research Article Pulmonology

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

Abstract

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.

Authors

Melissa Y. Tjota, Jesse W. Williams, Tiffany Lu, Bryan S. Clay, Tiara Byrd, Cara L. Hrusch, Donna C. Decker, Claudia Alves de Araujo, Paul J. Bryce, Anne I. Sperling

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Figure 3

IC signaling through FcγRIII leads to a significant upregulation of IL-33 in WT APCs.

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IC signaling through FcγRIII leads to a significant upregulation of IL-3...
(A) BMDCs generated from WT or Fcgr3–/– mice were treated with OVA or OVA-IC overnight, and Il33 mRNA expression normalized to B2m mRNA expression was assessed by qPCR. (B) Multiplex array for IL-33 protein from OVA- or OVA-IC–treated WT, Fcgr3–/–, and Il33–/– BMDCs. (C) FcγRIII expression was assessed on naive WT AMs and rDCs, as gated in Supplemental Figure 4 (red, unstained; blue, AMs; green, rDCs). (D) Il33 mRNA expression in AMs and rDCs sorted from WT and Fcgr3–/– mice 3 hours after i.t. challenge with OVA or OVA-IC. (E) FcγRIII expression was assessed on rDC subpopulations (CD103+ and CD11b+ rDCs) from naive WT lungs (red, unstained; blue, CD103+ rDCs; green, CD11b+ rDCs). (F) WT mice were challenged i.t. with OVA-APC or OVA-APC IC, and OVA-APC expression on WT lung APCs was analyzed 3 hours after challenge (red, unchallenged; blue, OVA-APC; green; OVA-APC IC). (G) WT mice were challenged i.t. with OVA-IC, and rDC subpopulations were sorted 3 hours later. Il33 mRNA expression was determined by qPCR. The data in A, B, D, and G are from 3 independent experiments. Symbols represent independent experiments, horizontal bars indicate the mean, and error bars indicate SEM (*P < 0.05; **P < 0.01; ***P < 0.001). C, E, and F show representative flow plots, with at least 6 mice analyzed per group.