Abstract
The role of T-helper type 17 (Th17) responses in airway remodeling in asthma is currently unknown. We demonstrate that both parenteral and mucosal allergen sensitization, followed by allergen inhalation, leads to Th17-biased lung immune responses. Unlike Th17 cells generated in vitro, lung Th17 cells did not produce tumor necrosis factor-α or interleukin (IL)-22. Eosinophilia predominated in acute inflammation, while neutrophilia and IL-17 increased in chronic disease. Allergen-induced tolerance involved Foxp3-, Helios-, and glycoprotein-A repetitions predominant-expressing regulatory T cells (Treg) and IL-10/interferon-γ priming. This Treg phenotype was altered in inflamed lungs and abrogated by inhalation of IL-17. Using Th17-deficient mice with genetic disruption of gp130 in T cells, we showed that Th17 cells induce airway remodeling independent of the Th2 response. All-trans retinoic acid administration ameliorated Th17-mediated disease and increased Treg activity, while dexamethasone inhibited eosinophilia but not neutrophilia, and enhanced Th17 development in vitro. Targeting the Th17/Treg axis might therefore be therapeutic in neutrophilic and glucocorticoid-refractory asthma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Airway Remodeling / immunology*
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Allergens / immunology
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Animals
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Asthma / immunology
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Asthma / pathology
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Cell Differentiation / drug effects
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Cell Differentiation / immunology
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DNA-Binding Proteins / metabolism
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Dexamethasone / pharmacology
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Immune Tolerance*
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Inflammation / immunology
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Inflammation / metabolism
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Inflammation / pathology
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Interferon-gamma / biosynthesis
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Interleukin-10 / biosynthesis
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Interleukin-17 / immunology
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Lung / immunology
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Lung / pathology
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Mice
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Mice, Knockout
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Permeability
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Phenotype
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Respiratory Mucosa / immunology
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Respiratory Mucosa / metabolism
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Respiratory Mucosa / pathology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
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Th17 Cells / cytology
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Th17 Cells / drug effects
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Th17 Cells / immunology*
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Th17 Cells / metabolism
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Th2 Cells / immunology
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Th2 Cells / metabolism
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Transcription Factors / metabolism
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Tretinoin / pharmacology
Substances
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Allergens
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DNA-Binding Proteins
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Interleukin-17
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Transcription Factors
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Zfpn1a2 protein, mouse
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Interleukin-10
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Tretinoin
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Dexamethasone
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Interferon-gamma