Molecular Mechanisms of Airway Hyperresponsiveness in a Murine Model of Steroid-Resistant Airway Inflammation

• Published in: The Journal of immunology (1950) Vol. 196; no. 3; pp. 963 - 977
• Main Authors: Manni, Michelle L, Mandalapu, Sivanarayana, McHugh, Kevin J, Elloso, M Merle, Dudas, Paul L, Alcorn, John F
• Format: Journal Article
• Language: English
• Published: United States 01.02.2016
• Subjects: Adoptive Transfer; Animals; Asthma - immunology; Asthma - pathology; Disease Models, Animal; Drug Resistance; Immunoblotting; Interleukin-13 - immunology; Interleukin-17 - immunology; Metaplasia - immunology; Metaplasia - pathology; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, SCID; Mice, Transgenic; Mucus - immunology; Polymerase Chain Reaction; Respiratory Hypersensitivity - immunology; Respiratory Hypersensitivity - pathology; Th17 Cells - immunology; Th2 Cells - immunology; Transcriptome
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1501531

IL-13 and IL-17A, produced mainly by Th2 and Th17 cells, respectively, have an influential role in asthma pathogenesis. We examined the role of IL-13 and IL-17A in mediating airway hyperresponsiveness (AHR), lung inflammation, and mucus metaplasia in a dual Th2/Th17 model of asthma. IL-13 and/or IL-17A were neutralized using mAbs. Th2/Th17 adoptive transfer induced a mixed asthma phenotype characterized by elevated eosinophilia and neutrophilia, tissue inflammation, mucus metaplasia, and AHR that were partially reversible with steroid treatment. Pulmonary inflammation and quasi-static lung compliance were largely unaffected by neutralization of IL-13 and/or IL-17A. However, neutralization of IL-13 alone or in combination with IL-17A significantly attenuated AHR and mucus metaplasia. Further, STAT6 activation was attenuated following IL-13 and IL-13/IL-17A Ab treatment. We next assessed the role of STAT6 in Th2/Th17-mediated allergic airway disease using STAT6(-/-) mice. STAT6(-/-) mice adoptively transferred with Th2/Th17 cells had decreased AHR compared with controls. These data suggest that IL-13 drives AHR and mucus metaplasia in a STAT6-dependent manner, without directly contributing to airway or tissue inflammation. IL-17A independently contributes to AHR, but it only partially mediates inflammation and mucus metaplasia in a mixed Th2/Th17 model of steroid-resistant asthma.