Abstract
Aquaporin 3 (AQP3), a water/glycerol channel protein, has been found to transport hydrogen peroxide (H2O2). Here, we show that H2O2, 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.
Highlights
Aquaporin 3 (AQP3), a water/glycerol channel protein, has been found to transport hydrogen peroxide (H2O2)
Building on a study reporting AQP3-facilitated cellular uptake of H2O2, a reactive oxygen species (ROS), we reported the involvement of AQP3-mediated H2O2 in T-cell signalling in cutaneous contact hypersensitivity[16]
We showed that extracellular H2O2 produced in response to CXCL12 stimulation was transported into T cells by AQP3, which facilitated CXCL12dependent cell signalling and T cell migration
Summary
Aquaporin 3 (AQP3), a water/glycerol channel protein, has been found to transport hydrogen peroxide (H2O2). As AQP3 associates with Nox[2], we propose that this interplay constitutes H2O2-mediated signalling in response to TNF-a stimulation These data indicate that AQP3-facilitated H2O2 transport is required for NF-kB activation in keratinocytes in the development of psoriasis. Previous studies have shown the involvement of AQP3 expression in skin diseases, including wound healing, tumorigenesis and atopic dermatitis, in which their pathogenesis was attributed to the AQP3 water or glycerol transport function in epidermal keratinocytes[12,13,14]. We report here that AQP3 is required for TNF-a-induced NF-kB activation in keratinocytes and the development of psoriasis by a mechanism involving TNF-a-induced generation of extracellular H2O2 followed by its intracellular transport by AQP3. An in vivo mouse model of psoriasis showed remarkably reduced pathology in an AQP3-deficient background, in which continuous NF-kB activation and a higher H2O2 level in epidermal keratinocytes were suppressed by AQP3 deficiency
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