Requirement of aquaporin-3-mediated hydrogen peroxide for NF-κB cell signaling and psoriasis pathogenesis

Abstract

Aquaporin 3 (AQP3), a water/glycerol channel protein, has been recently shown to transport hydrogen peroxide (H2O2). Here we show that AQP3-mediated H2O2 is involved in nuclear factor-κB (NF-κB) cell signaling in keratinocytes and in the pathogenesis of psoriasis. In in vitro studies with primary keratinocytes from wild-type and AQP3 knockout (AQP3−/−) mice, the extracellular H2O2 generated by membrane NADPH oxidase 2 (Nox2) activation in response to TNF-α was intracellularly transported via AQP3, which was indispensable for the activation of NF-κB. We found the association of AQP3 with Nox2 in membrane fraction that might facilitate the transient increase in intracellular H2O2 levels around membranes after TNF-α stimulation. Coincidentally, AQP3−/− mice was impaired in the development of psoriasis in vivo mouse model which was partially dependent on TNF-α-mediated cell signaling, in which continuous NF-κB activation and a higher H2O2 level in keratinocytes were found to be suppressed by AQP3 deficiency. These data reveal that AQP3-mediated H2O2 is required for NF-κB activation in keratinocytes during psoriasis development. Our findings provide novel insights into the pathogenesis of psoriasis and may provide a basis for new therapies.