Aquaporin-3-mediated hydrogen peroxide transport is required for NF-κB signalling in keratinocytes and development of psoriasis

Abstract

Aquaporin 3 (AQP3), a water/glycerol channel protein, has been found to transport hydrogen peroxide (H ₂O ₂). Here, we show that H ₂O _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 H ₂O ₂ accumulation. In primary keratinocyte cultures, cellular import of H ₂O ₂ 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 H ₂O ₂-mediated signalling in response to TNF-α stimulation. Collectively, these data indicate that AQP3-facilitated H ₂O ₂ transport is required for NF-κB activation in keratinocytes in the development of psoriasis.