Maintenance of Airway Hyperresponsiveness in Chronic Asthma May Be Mediated by Th2-Independent Mechanisms

Nora J. Lin1, Jane M. Schuh2, Cory Hogaboam*, 2
1 Division of Allergy & Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
2 Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA

© 2008 Li et al;

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; E-mail:


CD4+, Th2-mediated inflammation is an important component of airway hyperresponsiveness (AHR) in allergic airway disease. IL-4 specifically interacts with the Type 1 IL-4 receptor comprised of IL-4Rα and the common γ chain, whereas IL-4 and IL-13 mediate their effects through a common receptor complex made up of IL-4Rα and IL- 13Rα1 (i.e. the Type II IL-4 receptor). In this study, we examined the effects of impaired Th2 signaling on AHR using IL4Rα-/- mice in a murine model of allergic asthma. IL-4Rα-/- mice and control BALB/c (IL-4Rα+/+) mice were sensitized to and challenged with Aspergillus fumigatus. Airway disease was assessed at days 14, 28, 51, and 57 after intratracheal conidia challenge. AHR was evaluated by plethysmography after intravenous methacholine. Whole lung levels of cytokines and chemokines, and serum immunoglobulins were measured by specific ELISA. Paraffin-embedded lung sections were stained for histology. Bronchoalveolar lavage (BAL) fluid was cytospun for differential cell counts. While AHR was significantly reduced in IL-4Rα-/- mice (p<0.01) at days 14 and 28 after conidia challenge, it was increased when compared to controls at later time points (days 51 and 57) even though Th2 cytokines were significantly decreased at day 57, and total IgE and IgG1 levels were markedly decreased throughout the study (p<0.0001). Goblet cell metaplasia was also evident at days 51 and 57 in the knockout groups. These results demonstrate that airway hyperresponsiveness and mucus cell metaplasia in a model of allergic asthma can develop in the absence of a predominant Th2 signaling pathway, suggesting that Th2-independent mechanisms may arbitrate chronic stages of airway disease due to A. fumigatus.

Keywords: Th1/Th2, asthma, mice, IL-4Rα.