IL-22 promotes allergic airway inflammation in epicutaneously sensitized mice

• Published in: Journal of allergy and clinical immunology Vol. 143; no. 2; pp. 619 - 630.e7
• Main Authors: Leyva-Castillo, Juan Manuel, Yoon, Juhan, Geha, Raif S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2019
• Subjects: Allergens - immunology; Animals; asthma; Asthma - immunology; atopic dermatitis; Dermatitis, Atopic - immunology; Disease Models, Animal; Humans; Hypersensitivity - immunology; IL-22; Immunization; Inflammation - immunology; Interleukin-22; Interleukins - genetics; Interleukins - metabolism; Mice; Mice, Inbred BALB C; Mice, Knockout; neutrophils; Ovalbumin - immunology; Respiratory Hypersensitivity; Skin - pathology; Th2 Cells - immunology; ILC; TCR; AD; BALF; atopic dermatitis; asthma; AHR; IL-22; ILC1; APC; OVA; neutrophils; WT; DC
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2018.05.032

Serum IL-22 levels are increased in patients with atopic dermatitis, which commonly precedes asthma in the atopic march. Epicutaneous sensitization in mice results in TH2-dominated skin inflammation that mimics atopic dermatitis and sensitizes the airways for antigen challenge–induced allergic inflammation characterized by the presence of both eosinophils and neutrophils. Epicutaneous sensitization results in increased serum levels of IL-22. We sought to determine the role of IL-22 in antigen-driven airway allergic inflammation after inhalation challenge in epicutaneously sensitized mice. Wild-type (WT) and Il22−/− mice were sensitized epicutaneously or immunized intraperitoneally with ovalbumin (OVA) and challenged intranasally with antigen. OVA T-cell receptor–specific T cells were TH22 polarized in vitro. Airway inflammation, mRNA levels in the lungs, and airway hyperresponsiveness (AHR) were examined. Epicutaneous sensitization preferentially elicited an IL-22 response compared with intraperitoneal immunization. Intranasal challenge of mice epicutaneously sensitized with OVA elicited in the lungs Il22 mRNA expression, IL-22 production, and accumulation of CD3+CD4+IL-22+ T cells that coexpressed IL-17A and TNF-α. Epicutaneously sensitized Il22−/− mice exhibited diminished eosinophil and neutrophil airway infiltration and decreased AHR after intranasal OVA challenge. Production of IL-13, IL-17A, and TNF-α was normal, but IFN-γ production was increased in lung cells from airway-challenged and epicutaneously sensitized Il22−/− mice. Intranasal instillation of IFN-γ–neutralizing antibody partially reversed the defect in eosinophil recruitment. WT recipients of TH22-polarized WT, but not IL-22–deficient, T-cell receptor OVA-specific T cells, which secrete both IL-17A and TNF-α, had neutrophil-dominated airway inflammation and AHR on intranasal OVA challenge. Intranasal instillation of IL-22 with TNF-α, but not IL-17A, elicited neutrophil-dominated airway inflammation and AHR in WT mice, suggesting that loss of IL-22 synergy with TNF-α contributed to defective recruitment of neutrophils into the airways of Il22−/− mice. TNF-α, but not IL-22, blockade at the time of antigen inhalation challenge inhibited airway inflammation in epicutaneously sensitized mice. Epicutaneous sensitization promotes generation of antigen-specific IL-22–producing T cells that promote airway inflammation and AHR after antigen challenge, suggesting that IL-22 plays an important role in the atopic march. [Display omitted]