Exaggerated IL-17 response to epicutaneous sensitization mediates airway inflammation in the absence of IL-4 and IL-13

Rui He, Hye Young Kim, Juhan Yoon, Michiko K. Oyoshi, Andrew MacGinnitie, Sho Goya, Eva Jasmin Freyschmidt, Paul Bryce, Andrew N J McKenzie, Dale T. Umetsu, Hans C. Oettgen, Raif S. Geha*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

Abstract

Background: Atopic dermatitis (AD) is characterized by local and systemic TH2 responses to cutaneously introduced allergens and is a risk factor for asthma. Blockade of TH2 cytokines has been suggested as therapy for AD. Objectives: We sought to examine the effect of the absence of IL-4 and IL-13 on the TH17 response to epicutaneous sensitization in a murine model of allergic skin inflammation with features of AD. Methods: Wild-type, IL4 knockout (KO), IL13 KO and IL4/13 double KO (DKO) mice were subjected to epicutaneous sensitization with ovalbumin (OVA) or saline and airway challenged with OVA. Systemic immune responses to OVA, skin and airway inflammation, and airway hyperresponsiveness were examined. Results: OVA-sensitized DKO mice exhibited impaired TH2-driven responses with undetectable OVA-specific IgE levels and severely diminished eosinophil infiltration at sensitized skin sites but intact dermal infiltration with CD4+ cells. DKO mice mounted exaggerated IL-17A but normal IFN-γ and IL-5 systemic responses. Airway challenge of these mice with OVA caused marked upregulation of IL-17 mRNA expression in the lungs, increased neutrophilia in bronchoalveolar lavage fluid, airway inflammation characterized by mononuclear cell infiltration with no detectable eosinophils, and bronchial hyperresponsiveness to methacholine that were reversed by IL-17 blockade. IL-4, but not IL-13, was identified as the major TH2 cytokine that downregulates the IL-17 response in epicutaneously sensitized mice. Conclusion: Epicutaneous sensitization in the absence of IL-4/IL-13 induces an exaggerated TH17 response systemically and in lungs after antigen challenge that results in airway inflammation and airway hyperresponsiveness.

Original languageEnglish (US)
Pages (from-to)761-770.e1
JournalJournal of Allergy and Clinical Immunology
Volume124
Issue number4
DOIs
StatePublished - Oct 2009

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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