House dust mite induced allergic airway disease is attenuated in CD11ccreIL-4R\u03b1\u2212/l\xb0x mice

Natalie Eva Nieuwenhuizen,Frank Brombacher,Frank Kirstein,Jennifer Claire Hoving

doi:10.1038/s41598-017-19060-9

Abstract

The precise mechanisms leading to development of T helper type (Th)2-driven allergic responses are unknown. We aimed to determine how IL-4 receptor alpha (IL-4Rα) signaling on CD11c+ cells influences allergen-induced Th2 responses in mice. CD11ccreIL-4Rα−/l°x mice, deficient in IL-4Rα on dendritic cells and alveolar macrophages, were compared to IL-4Rα−/l°x littermate controls in models of allergic airway disease induced by OVA/alum, OVA alone or house dust mite. Cytokine responses, eosinophil and neutrophil infiltration into the lungs, airway hyperreactivity and mucus hypersecretion were evaluated after allergen challenge. In the OVA/alum model, CD11ccreIL-4Rα−/lox mice had similar airway hyperreactivity, eosinophil infiltration, Th2-type cytokine production and mucus hypersecretion to littermate controls. When alum was omitted during sensitization, CD11ccreIL-4Rα−/lox mice had similar airway hyperreactivity and mucus secretion but reduced Th2-type cytokine production and eosinophils, suggesting alum overrides the requirement for IL-4Rα signaling on CD11c+ cells in enhancing Th2-type responses. In the house dust mite model, CD11ccreIL-4Rα−/lox mice showed similar mucus secretion, but reduced Th2 responses, eosinophils, neutrophils and airway hyperreactivity, unlike previously tested LysMcreIL-4Rα−/lox mice, which lack IL-4Rα on alveolar macrophages but not on dendritic cells. Therefore, our results indicate that IL-4Rα signaling on dendritic cells promotes allergen-induced Th2 responses and eosinophil infiltration into the lung.

Highlights

The precise mechanisms leading to development of T helper type (Th)2-driven allergic responses are unknown
We have shown that CD11ccreIL-4Rα−/lox mice lack IL-4Rα expression on Dendritic cells (DCs) and alveolar macrophages[10], we aimed to determine whether IL-4Rα signaling on DCs is important in allergic disease of the airways by using CD11ccreIL-4Rα−/lox mice
Allergic inflammation was similar in CD11ccreIL-4Rα−/lox mice compared to littermate controls, as seen by similar frequencies of eosinophils in bronchiolar lavage fluid and similar numbers of eosinophils in the lung, neutrophils tended to be decreased in CD11ccreIL-4Rα−/lox mice (Fig. 1B)

Summary

Introduction

The precise mechanisms leading to development of T helper type (Th)2-driven allergic responses are unknown. When alum was omitted during sensitization, CD11ccreIL-4Rα−/lox mice had similar airway hyperreactivity and mucus secretion but reduced Th2-type cytokine production and eosinophils, suggesting alum overrides the requirement for IL-4Rα signaling on CD11c+ cells in enhancing Th2-type responses. In the house dust mite model, CD11ccreIL-4Rα−/lox mice showed similar mucus secretion, but reduced Th2 responses, eosinophils, neutrophils and airway hyperreactivity, unlike previously tested LysMcreIL-4Rα−/lox mice, which lack IL-4Rα on alveolar macrophages but not on dendritic cells. While the signals that drive DC driven induction of Th1 and Th17 responses are well understood, the mechanisms leading to the Th2 differentiation observed in allergic disease and helminth infection are still unclear[1] It is well-established that IL-4 plays an important role[1,2], and in the absence of DCs, Th2 responses are dramatically reduced[3]. The absence of IL-4Rα signaling on DCs significantly reduced eosinophils, neutrophils and airway hyperreactivity (AHR) in house dust mite-induced allergic airway disease, showing that IL-4 acts directly on DCs to exacerbate allergic airway disease

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