Skin barrier dysfunction and atopic dermatitis

Within the epidermis, barrier proteins including filaggrin, transglutaminases, keratins and loricrin, and intercellular proteins cross-link into clusters to form an impermeable barrier (Kim & Leung, 2018). This protects us from exogenous stressors and allergens, but also helps maintain internal fluid and electrolyte homeostasis. Disruption of the skin barrier enables the penetration of allergens that can trigger an immune response and may subsequently lead to the development of IgE-mediated allergies (McPherson, 2016). While skin barrier dysfunction is critical to the onset of atopic dermatitis, no individual cause has been identified. Instead, several factors contribute to the loss of skin barrier function.

Skin barrier dysfunction and atopic dermatitis.

Figure 7: Skin barrier dysfunction and atopic dermatitis (Peng & Novak, 2015).

Genetic, immunological, and mechanical factors lead to skin barrier dysfunction allowing activated antigen-presenting cells to encounter allergens, pathogens and environmental factors. This results in promotion of a Th2-mediated immune response further damaging the skin barrier and inducing keratinocyte apoptosis. Virulence factors released by colonising pathogens can also promote keratinocyte cell death and Th2-type inflammation further driving barrier dysfunction. DC, Dendritic cell; EO ceramides, ester-linked ω-hydroxy ceramides; FFAs, free fatty acids; IFN-γ, interferon-γ; IgE, immunoglobulin E; IL, interleukin; KLK7, kallikrein 7; LC, Langerhans cell; MCs, mast cells; MHC, major histocompatibility complex; TCR, T cell receptor; Th2, T helper 2 cells, TNFα, tumour necrosis factor α; TSLP, thymic stromal lymphopoietin; TWEAK, TNF-like weak inducer of apoptosis.

Epidermal barrier protein loss

While filaggrin plays an important role in the development of barrier protein clusters, it is also degraded upon exposure to low humidity into free amino acids, which are essential for maintaining skin pH and retaining water in the cornified layer (Scott & Harding, 1986; Denecker et al., 2007; Nicotera & Melino, 2007; Jang et al., 2016). Mutation of the filaggrin gene, FLG, is a well-known predisposing factor for atopic dermatitis development. Filaggrin deficiency has been shown to cause paracellular skin barrier abnormalities that reduce inflammatory thresholds to irritants and haptens (Kim & Leung, 2018). However, a significant number of patients with atopic dermatitis do not have a FLG mutation and approximately 40% of individuals with FLG-null alleles do not go on to develop atopic dermatitis (O’Regan et al., 2008; Kim & Leung, 2018). While FLG mutations clearly contribute to the development of atopic dermatitis in many people, it is not sufficient alone to generate the condition. Interestingly, FLG mutation is not the only means by which filaggrin levels are reduced. A Th2-type inflammatory response is typically observed in acute atopic dermatitis and the Th2 cytokines IL-17, IL-22, IL-25 and IL-31 are capable of downregulating filaggrin expression. Indeed, while filaggrin mutations are observed in about one-third of Caucasian patients with atopic dermatitis, skin barrier impairment and reduced filaggrin expression are seen in most patients (Peng & Novak, 2015).

Tight junctions, desmosomes and adherens junctions form adhesions between the cells of the epidermis to help create a physical, permeability barrier. The Th2 cytokines that downregulate filaggrin expression have also been shown to downregulate the proteins involved in tight junction formation resulting in increased transepidermal water loss, greater allergen and microbial penetration of the skin and reduced skin barrier cohesion (De Benedetto et al., 2011; Gruber et al., 2015; Kim & Leung, 2018).

Antimicrobial peptides (AMPs) and dysbiosis

During infection, inflammation and wounding, keratinocytes express a range of AMPs that form an innate chemical barrier to microbes. However, the presence of Th2 cytokines in atopic dermatitis downregulates their expression and has been associated with an increased risk of S. aureus infection, which can further exacerbate atopic dermatitis (Kim & Leung, 2018). Cutaneous dysbiosis can cause skin inflammation and barrier dysfunction and result in recurrent infection and increased skin pH (Elias et al., 2008; Ali & Yosipovitch, 2013; Leung, 2013).

Lipid matrix

The presence of S. aureus as well as Th2 cytokines has also been shown to modify the expression of enzymes involved in the biosynthesis of long-chain free fatty acids and ceramides within the skin further impacting skin barrier function (Danso et al., 2017; Ito et al., 2017; Kim et al., 2017; Li et al., 2017).

Keratinocyte cell death and damage

With skin barrier function reduced, the subsequent immune response can exacerbate dysfunction and promote physical damage. Increased expression of TNFα and TNF-like weak inducer of apoptosis (TWEAK) promotes keratinocyte apoptosis and development of skin lesions (Zimmermann et al., 2011). In addition, the keratinocytes of patients with atopic dermatitis have been shown to be more susceptible to IFN-γ-induced apoptosis compared to healthy controls (Rebane et al., 2012). Further damage to the skin barrier can be caused by scratching. Pruritus is a hallmark feature of atopic dermatitis, however, scratching further irritates the skin exacerbating the itching (Eichenfield et al., 2014).