Aquaporins Are One of the Critical Factors in the Disruption of the Skin Barrier in Inflammatory Skin Diseases

Abstract

The skin is the largest organ of the human body, serving as an effective mechanical barrier between the internal milieu and the external environment. The skin is widely considered the first-line defence of the body, with an essential function in rejecting pathogens and preventing mechanical, chemical, and physical damages. Keratinocytes are the predominant cells of the outer skin layer, the epidermis, which acts as a mechanical and water-permeability barrier. The epidermis is a permanently renewed tissue where undifferentiated keratinocytes located at the basal layer proliferate and migrate to the overlying layers. During this migration process, keratinocytes undertake a differentiation program known as keratinization process. Dysregulation of this differentiation process can result in a series of skin disorders. In this context, aquaporins (AQPs), a family of membrane channel proteins allowing the movement of water and small neutral solutes, are emerging as important players in skin physiology and skin diseases. Here, we review the role of AQPs in skin keratinization, hydration, keratinocytes proliferation, water retention, barrier repair, wound healing, and immune response activation. We also discuss the dysregulated involvement of AQPs in some common inflammatory dermatological diseases characterised by skin barrier disruption.

Keywords: AQP3; aquaporin channels; atopic dermatitis; hidradenitis suppurativa; membrane transport; psoriasis.

Figure 1

Schematic representation of skin barrier functions. The chemical barrier is mainly due to natural moisturizing factors (NMF) and epidermal lipids in the stratum corneum. The physical barrier is accomplished thanks to tight junctions and desmosomes in the granular and spinous layers. The immune barrier is carried on by skin-resident immune cells in the epidermis and dermis such as Langerhans cells and dermal dendritic cells, macrophages, resident T cells, and mast cells, respectively, and by epidermal keratinocytes.

Figure 2

Immunofluorescence distribution of AQP3 in normal human epidermis. Shown is immunofluorescence analysis of AQP3 labelling in the epidermis of a normal human subject. Skin tissue was formalin-fixed and paraffin-embedded. Sections were stained using an anti-human AQP3 antibody recognizing AQP3 (Thermo Fisher Scientific, Monza, Italy). Cell nuclei were stained with DAPI (blue fluorescence). Strong AQP3 immunoreactivity (green fluorescence) is seen over the plasma membrane of stratum basale (SB) and stratum spinosum (SS) keratinocytes (arrows). Weak intracellular immunoreactivity is observed in the intracellular compartment (asterisks). The plasma membrane immunostaining of SG keratinocytes is lower than the one of the underlying epidermal layers (double arrowheads). No immunofluorescence is seen in the stratum corneum (SC) of the epidermis and in the dermis.

Figure 3

Graphical representation of the main pathophyioslogical roles suggested for AQP5, AQP9, and AQP3 in hidradenitis suppurativa, atopic dermatitis, and psoriasis, respectively.