Abstract
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.
Highlights
IL-4 and IL-13 are considered to be key players in the pathophysiology of asthma and allergic disorders, their individual roles are still unclear
We showed that in an established model of chronic asthma, deficiency of the IL4R chain in A. fumigatus-sensitized mice did not result in the long-term elimination of airway hyperresponsiveness (AHR) and goblet cell metaplasia as might be expected given the previously established importance of IL-4 and IL-13 signaling in the pathogenesis of asthma [14, 15, 18,19,20]
We observed that IL4R-/- mice had increased AHR and mucus cell metaplasia in the more chronic stages of disease but not in the earlier stages
Summary
IL-4 and IL-13 are considered to be key players in the pathophysiology of asthma and allergic disorders, their individual roles are still unclear. IL-4 binds with high affinity to the 140-kD IL4R chain, and subsequent dimerization with the common gamma chain (c) forms the type I receptor, found on hematopoietic cells [1,6]. Formation of this IL4R/c heterodimer initiates signaling through the IL4R chain, leading to STAT6 activation and gene transcription [6]. The IL4R chain serves as a common signaling component of both the IL-4 and IL-13 receptors that explains much of their overlapping functions
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