Aquaporin 3 (AQP3), a water/glycerol channel protein, has been found to transport hydrogen peroxide (H₂O₂). Here, we show that H₂O_2, imported via AQP3, is involved in nuclear factor-κB (NF-κB) signalling in keratinocytes and in the pathogenesis of psoriasis. IL-23-mediated induction of psoriasis is reduced in AQP3 knockout mice (AQP3^−/−), and is accompanied by impaired NF-κB activation and intracellular H₂O₂ accumulation. In primary keratinocyte cultures, cellular import of H₂O₂ produced by membrane NADPH oxidase 2 (Nox2) in response to TNF-α is facilitated by AQP3 and required for NF-κB activation by regulation of protein phosphatase 2A. As AQP3 associates with Nox2, we propose that this interplay constitutes H₂O₂-mediated signalling in response to TNF-α stimulation. Collectively, these data indicate that AQP3-facilitated H₂O₂ transport is required for NF-κB activation in keratinocytes in the development of psoriasis.

Chemokine-dependent trafficking is indispensable for the effector function of antigen-experienced T cells during immune responses. In this study, we report that the water/glycerol channel aquaporin-3 (AQP3) is expressed on T cells and regulates their trafficking in cutaneous immune reactions. T cell migration toward chemokines is dependent on AQP3-mediated hydrogen peroxide (H2O2) uptake but not the canonical water/glycerol transport. AQP3-mediated H2O2 transport is essential for the activation of the Rho family GTPase Cdc42 and the subsequent actin dynamics. Coincidentally, AQP3-deficient mice are defective in the development of hapten-induced contact hypersensitivity, which is attributed to the impaired trafficking of antigen-primed T cells to the hapten-challenged skin. We therefore suggest that AQP3-mediated H2O2 uptake is required for chemokine-dependent T cell migration in sufficient immune response.

Most of breast cancer mortality is due to clinical relapse associated with metastasis. CXCL12/CXCR4-dependent cell migration is a critical process in breast cancer progression; however, its underlying mechanism remains to be elucidated. Here, we show that the water/glycerol channel protein aquaporin-3 (AQP3) is required for CXCL12/CXCR4-dependent breast cancer cell migration through a mechanism involving its hydrogen peroxide (H₂O₂) transport function. Extracellular H₂O₂, produced by CXCL12-activated membrane NADPH oxidase 2 (Nox2), was transported into breast cancer cells via AQP3. Transient H₂O₂ accumulation was observed around the membrane during CXCL12-induced migration, which may be facilitated by the association of AQP3 with Nox2. Intracellular H₂O₂ then oxidized PTEN and PTP1B followed by activation of the Akt pathway. This contributed to directional cell migration. The expression level of AQP3 in breast cancer cells was related to their migration ability both in vitro and in vivo through CXCL12/CXCR4- or H₂O₂-dependent pathways. Coincidentally, spontaneous metastasis of orthotopic xenografts to lung was reduced upon AQP3 knockdown. These findings underscore the importance of AQP3-transported H₂O₂ in CXCL12/CXCR4-dependent signaling and migration in breast cancer cells, and suggest that AQP3 has potential as a therapeutic target for breast cancer.