Aquaporin-3 potentiates allergic airway inflammation in ovalbumin-induced murine asthma.

Kohei Ikezoe,Tomohiro Handa,Xiaojun Ma,Tetsuya Honda,Kazuo Chin,Yoshio Taguchi,Shuh Narumiya,Mariko Hara-Chikuma,Alan S Verkman,Kazuko Uno,Jun-Ichi Fuchikami,Tatsuaki Tsuruyama,Michiaki Mishima,Toru Oga,Kiminobu Tanizawa

doi:10.1038/srep25781

Abstract

Oxidative stress plays a pivotal role in the pathogenesis of asthma. Aquaporin-3 (AQP3) is a small transmembrane water/glycerol channel that may facilitate the membrane uptake of hydrogen peroxide (H2O2). Here we report that AQP3 potentiates ovalbumin (OVA)-induced murine asthma by mediating both chemokine production from alveolar macrophages and T cell trafficking. AQP3 deficient (AQP3−/−) mice exhibited significantly reduced airway inflammation compared to wild-type mice. Adoptive transfer experiments showed reduced airway eosinophilic inflammation in mice receiving OVA-sensitized splenocytes from AQP3−/− mice compared with wild-type mice after OVA challenge, consistently with fewer CD4+ T cells from AQP3−/− mice migrating to the lung than from wild-type mice. Additionally, in vivo and vitro experiments indicated that AQP3 induced the production of some chemokines such as CCL24 and CCL22 through regulating the amount of cellular H2O2 in M2 polarized alveolar macrophages. These results imply a critical role of AQP3 in asthma, and AQP3 may be a novel therapeutic target.

Highlights

Aquaporins (AQPs) are small integral membrane proteins that transport water across cell plasma membranes[6]
After following the procedure for sensitization and challenge shown in Supplementary Fig. S1a, we compared OVA-induced allergic asthma between AQP3−/− mice and wild-type (WT) mice by assessing airway inflammation using cell counts and lung sections, by evaluating airway responsiveness to methacholine, and by measuring concentrations of immunoglobulin E (IgE) and Th2 cytokines
Our results suggest that AQP3 potentiates asthma through mediating T cell trafficking and chemokine production from M2 polarized alveolar macrophages (AMs) by regulating the amount of cellular H2O2

Summary

Introduction

Aquaporins (AQPs) are small integral membrane proteins that transport water across cell plasma membranes[6]. Aquaglyceroporins, including aquaporin-3 (AQP3), transport small uncharged molecules such as glycerol. As to its physiological roles, AQP3 is known to be essential for the urinary-concentrating mechanism in the kidney, and AQP3-mediated glycerol transport is important for skin hydration[8,9]. We have reported that AQP3-mediated H2O2 uptake is essential for chemokine-dependent T cell migration[11]. We hypothesized that AQP3 would contribute to the pathogenesis of asthma by regulating the amount of cellular H2O2. We tested this hypothesis using AQP3 deficient (AQP3−/−) mice in an ovalbumin (OVA)-induced murine asthma model. We determined that AQP3 facilitated murine asthma through mediating chemokine production from alveolar macrophages (AMs) as well as regulating T cell trafficking

Methods

Results

Conclusion