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

Asthma is characterized by chronic inflammation of the airways where many cells and cellular elements are involved, and is associated with increased airway hyperresponsiveness (AHR). Although eosinophilic inflammation is a characteristic feature of asthma, T cells recruited into the airways orchestrate the inflammatory reaction through their secretion of cytokines and other mediators1. T helper type 2 (Th2) cytokines, such as interleukin (IL)-4 and IL-13, are involved in the class-switching of B cells to immunoglobulin E (IgE) synthesis, recruitment of mast cells, and maturation of eosinophils and basophils2. IL-4 and IL-13 can also induce the polarization of macrophages to alternatively activated macrophages (M2 macrophages). M2 macrophages are important in the attraction of cells to inflammatory foci, suppression of Th1 responses, sampling of the microenvironment by endocytosis, and orchestration of tissue repair3. Oxidative stress plays a pivotal role in the pathogenesis of asthma. Reactive oxygen species (ROS), including hydrogen peroxide (H2O2), may initiate and augment airway inflammation4. ROS increase airway smooth muscle contraction and stimulate mucin secretion. Many cell types, including lymphocytes and macrophages, are involved in the increased production of ROS in asthma. Recently, oxidative stress was suggested to be an important factor in the development of corticosteroid insensitivity, in relation to severe asthma5. Aquaporins (AQPs) are small integral membrane proteins that transport water across cell plasma membranes6. Of these, aquaglyceroporins, including aquaporin-3 (AQP3), also transport small uncharged molecules such as glycerol. AQP3 is localized in various tissues, including the kidney, skin, gastrointestinal tract, and respiratory tract7. 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 hydration8,9. Recently, AQP3 was found to facilitate the membrane uptake of H2O2, and influence the downstream cell signaling cascade in mammalian cells10. We also have reported that AQP3-mediated H2O2 uptake is essential for chemokine-dependent T cell migration11. AQP3 expression was shown to be upregulated in some murine asthma models12,13, although its role remains unknown. 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. Further, we then determined that AQP3 facilitated murine asthma through mediating chemokine production from alveolar macrophages (AMs) as well as regulating T cell trafficking.