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

Melissa Y. Tjota, Cara L. Hrusch, Kelly M. Blaine, Jesse W. Williams, Nora A. Barrett, Anne I. Sperling

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)706-713.e8
JournalThe Journal of Allergy and Clinical Immunology
Issue number3
StatePublished - Sep 1 2014
Externally publishedYes

Bibliographical note

Funding Information:
Disclosure of potential conflict of interest: M. Y. Tjota has received travel support from the American Association of Immunologists . C. L. Hrusch has received research support from the National Institutes of Health and is employed by the University of Chicago. A. I. Sperling has received research support from the National Institutes of Health . The rest of the authors declare that they have no relevant conflicts of interest.

Funding Information:
Supported by National Institutes of Health (NIH) grants R21AI094408 (to A.I.S.), K08AI080948 (to N.A.B.), R01HL120952 (to N.A.B.), 5T32HL007605 (to C.L.H.), and 5T32HL007237 (to J.W.W.) and a Naomi Ragins-Goldsmith Fellowship from the University of Chicago (to M.Y.T.). The University of Chicago Cancer Center Core Facilities used are supported by National Institutes of Health grant P30CA14599 .

Publisher Copyright:
Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.


  • allergic airway inflammation
  • Dendritic cells
  • FcRγ
  • house dust mite
  • immune complexes
  • lungs
  • T(H)2


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