An Aquaporin 3-Notch1 Axis in Keratinocyte Differentiation and Inflammation

Liqiong Guo,Qixing Zhou,Hongxiang Chen,Yongsheng Li,Yang Sui,Andrzej T Slominski

doi:10.1371/journal.pone.0080179

Abstract

Aquaporin 3 (AQP3) is an aquaglyceroporin which transports water, glycerol and small solutes across the plasma membrane. Its functions are not limited to fluid transport but also involve the regulation of cell proliferation, migration, skin hydration, wound healing and tumorigenesis. While AQP3 has been reported to play an important role in keratinocyte proliferation, its role in differentiation remains controversial. Our study demonstrated that the expression of AQP3 was regulated during differentiation and that it participated in keratinocyte differentiation control. We further revealed that AQP3 was a transcriptional target of Notch signaling, a critical pathway regulating keratinocyte differentiation and tumor suppression, and it regulated differentiation through a reciprocal negative feedback loop with Notch1. When the expression level of AQP3 was elevated, impaired barrier integrity and increased pro-inflammatory cytokine production ensued, mimicking the pathological conditions in Notch deficient mice and in atopic dermatitis. Dysregulation of AQP3 and Notch receptors has been reported in several skin diseases, including skin cancer. Our discovery of the novel AQP3-Notch1 axis may provide insight into epidermal homeostasis control and possible translational applications, including its potential use as a biomarker for molecular diagnosis in environmental studies.

Highlights

The aquaporins are a family of transmembrane channels transporting water and in some cases, small solutes across the plasma membrane driven by osmotic gradients [1]
AQP3-mediated water and glycerol transport play an important role in a number of cellular and physiological processes in the epidermis, such as cell migration, proliferation, hydration, wound healing and tumorigenesis [38]
Our investigation of AQP3’s involvement in keratinocyte differentiation and its interconnection with Notch signaling was ignited by the conflicting results in the literature as well as the inverse expression patterns of Notch receptors and AQP3 in skin diseases [29,36,39,40]

Summary

Introduction

The aquaporins are a family of transmembrane channels transporting water and in some cases, small solutes across the plasma membrane driven by osmotic gradients [1]. Studies from aquaporin-null mice revealed important functions of aquaporins in urine concentration [2,3], brain water balance [4,5] and neuroexcitation [6,7,8], corneal transparency and retina swelling [9,10], skin hydration and elasticity [11,12], cell migration [13,14,15,16], cell proliferation [14,17], wound healing [15], angiogenesis [13] and fat metabolism [18]. Aquaporin-3 (AQP3) is the predominant and most widely studied aquaporin in mammalian skin It is an aquaglyceroporin and is capable of transporting water, glycerol, urea and hydrogen peroxide [1]. AQP3mediated glycerol transport plays an important role in stratum corneum hydration, skin elasticity, barrier recovery, wound healing and cell proliferation whereas AQP3-mediated water transport is critical for cell migration [11,15]. The interconnection between AQP3 and Notch may have general relevance in the physiological and pathological processes of the skin

Results

Discussion

Findings

Ethics Statement