IL-25 and IL-33 Contribute to Development of Eosinophilic Airway Inflammation in Epicutaneously Antigen-Sensitized Mice.

Hideaki Morita,Susumu Nakae,Takao Takahashi,Sumika Toyama,Akio Matsuda,Kenji Matsumoto,Hajime Suto,Hirotoshi Unno,Ko Okumura,Hirohisa Saito,Kenichiro Motomura,Katsuko Sudo,Ken Arae,Bernhard Ryffel

doi:10.1371/journal.pone.0134226

Abstract

BackgroundIL-25, IL-33 and TSLP are produced predominantly by epithelial cells and are known to induce Th2-type cytokines. Th2-type cytokines are involved not only in host defense against nematodes, but also in the development of Th2-type allergic diseases. TSLP was reported to be crucial for development of allergic airway inflammation in mice after inhalation of allergens to which they had been sensitized epicutaneously (EC) beforehand. However, the roles of IL-25 and IL-33 in the setting remain unclear.MethodsMice deficient in IL-25 and IL-33 were sensitized EC with ovalbumin (OVA) and then challenged intranasally with OVA. Airway inflammation, the number of inflammatory cells in bronchoalveolar lavage fluids (BALFs) and airway hyperresponsiveness (AHR) in the mice were determined, respectively, by histological analysis, with a hemocytometer, and by using plethysmograph chambers with a ventilator. Expression of mRNA in the skin and lungs was determined by quantitative PCR, while the BALF levels of myeloperoxidase (MPO) and eosinophil peroxidase (EPO) and the serum levels of IgE were determined by ELISA.Results Normal OVA-specific Th2- and Th17-cell responses of lymph nodes and spleens were observed in IL-25-deficient (IL-25-/-) and IL-33-/- mice after EC sensitization with OVA. Nevertheless, the number of eosinophils, but not neutrophils, in the BALFs, and the levels of Th2 cytokines, but not Th17 cytokines, in the lungs were significantly decreased in the IL-25-/- and IL-33-/- mice pre-sensitized EC with OVA, followed by inhalation of OVA, whereas their levels of AHR and OVA-specific serum IgE were normal.ConclusionsBoth IL-25 and IL-33 are critical for induction of Th2-type cytokine-mediated allergic airway eosinophilia, but not Th17-type cytokine-mediated airway neutrophilia, at the local sites of lungs in the challenge phase of mice sensitized EC with OVA. They do not affect OVA-specific T-cell induction in the sensitization phase.

Highlights

Sensitization with allergens via the upper and lower respiratory tracts due to dysfunction and/ or disruption of epithelial barriers is considered to be a major route of development of asthma [1]
Expression of mRNA in the skin and lungs was determined by quantitative PCR, while the bronchoalveolar lavage fluids (BALFs) levels of myeloperoxidase (MPO) and eosinophil peroxidase (EPO) and the serum levels of IgE were determined by ELISA
The number of eosinophils, but not neutrophils, in the BALFs, and the levels of Th2 cytokines, but not Th17 cytokines, in the lungs were significantly decreased in the IL-25-/- and IL-33-/- mice pre-sensitized EC with OVA, followed by inhalation of OVA, whereas their levels of airway hyperresponsiveness (AHR) and OVA-specific serum IgE were normal. Both IL-25 and IL-33 are critical for induction of Th2-type cytokine-mediated allergic airway eosinophilia, but not Th17-type cytokine-mediated airway neutrophilia, at the local sites of lungs in the challenge phase of mice sensitized EC with OVA

Summary

Introduction

Sensitization with allergens via the upper and lower respiratory tracts due to dysfunction and/ or disruption of epithelial barriers is considered to be a major route of development of asthma [1]. IL-25, IL-33 and/or TSLP were increased in specimens from patients with asthma [9,10,11] and in inflamed skin lesions of patients with atopic dermatitis [12,13,14,15] These cytokines may be produced by epithelial cells after exposure to allergens, contributing to the development of allergic diseases by inducing early immune responses leading to sensitization to allergens. It was reported that fulllength IL-33 can induce inflammation in an ST2-independent fashion [22] These observations suggest that IL-33-/- mice, rather than ST2-/- mice, should be used to elucidate the role of IL-33 in development of Th2-type airway inflammation in EC antigen-sensitized mice. TSLP was reported to be crucial for development of allergic airway inflammation in mice after inhalation of allergens to which they had been sensitized epicutaneously (EC) beforehand. The roles of IL-25 and IL-33 in the setting remain unclear

Methods

Results

Conclusion