Keratinocytes: innate immune cells in atopic dermatitis.

The skin is a unique immune organ that constitutes a complex network of physical, chemical and microbiological barriers against external insults. Keratinocytes are the most abundant cell type in the epidermis. These cells form the physical skin barrier and represent the first line of the host defense system by sensing pathogens via innate immune receptors, initiating anti-microbial responses and producing various cytokines, chemokines and anti-microbial peptides, which are important events in immunity. A damaged epidermal barrier in atopic dermatitis allows the penetration of potential allergens and pathogens to activate keratinocytes. Among the dysregulation of immune responses in atopic dermatitis, activated keratinocytes play a role in several biological processes that contribute to the pathogenesis of atopic dermatitis. In this review, we summarize the current understanding of the innate immune functions of keratinocytes in the pathogenesis of atopic dermatitis, with a special emphasis on skin-derived anti-microbial peptides and atopic dermatitis-related cytokines and chemokines in keratinocytes. An improved understanding of the innate immunity mediated by keratinocytes can provide helpful insight into the pathophysiological processes of atopic dermatitis and support new therapeutic efforts.

The role of human ß-defensins in allergic diseases.

Antimicrobial peptides (AMPs), also referred to as host defence peptides (HDPs), comprise a large family of small molecules broadly distributed throughout the animal and plant kingdom, historically serving as natural antibiotics. In mammals, there are two major families of AMPs/HDPs, the defensins and the cathelicidins. These peptides have evolved to protect against a wide range of infections from bacteria, viruses, fungi and some parasites. However, in addition to their broad-spectrum killing activities, AMPs/HDPs also possess various biological functions. They activate a variety of cell types, such as keratinocytes, airway epithelial cells and mast cells, among others, and regulate cytokine/chemokine production, cell migration, proliferation, differentiation, angiogenesis, the wound healing process and maintenance of the skin barrier function. Recently, it has become clear that alterations in the level of AMPs/HDPs are associated with the initiation and development of various inflammatory and allergic diseases. In this review, we will discuss the regulation and functions of human ß-defensins and outline the current evidence supporting the role of these peptides in the pathogenesis of allergic diseases, including atopic dermatitis, allergic rhinitis, asthma and chronic rhinosinusitis. Understanding the functions and mechanisms of human ß-defensins may aid in the development of novel therapeutic strategies for allergic diseases.

The antimicrobial protein S100A7/psoriasin enhances the expression of keratinocyte differentiation markers and strengthens the skin's tight junction barrier.

BACKGROUND: S100A7/psoriasin is a member of the S100 protein family and is encoded in the epidermal differentiation complex, which contains genes for markers of epidermal differentiation. S100A7/psoriasin is overexpressed in hyperproliferative skin diseases, where it is believed not only to exhibit antimicrobial functions, but also to induce immunomodulatory activities, including chemotaxis and cytokine/chemokine production. OBJECTIVES: To evaluate the effect of S100A7/psoriasin on keratinocyte differentiation and regulation of the tight junction (TJ) barrier. METHODS: Expression of differentiation markers and TJ proteins in human keratinocytes was determined by real-time polymerase chain reaction and Western blot. The changes in TJ barrier function were assessed by transepithelial electrical resistance and paracellular permeability assays. Glycogen synthase kinase-3 (GSK-3) and mitogen-activated protein kinase (MAPK) activation was analysed by Western blot, whereas ß-catenin and E-cadherin activation was evaluated by Western blot and immunofluorescence. RESULTS: S100A7/psoriasin enhanced the expression of several differentiation markers and selectively increased the expression of TJ proteins (e.g. claudins and occludin), which are known to strengthen the TJ barrier. Furthermore, S100A7/psoriasin increased ß-catenin and E-cadherin accumulation at cell-cell contact, and enhanced transepithelial electrical resistance while reducing the paracellular permeability of keratinocyte layers. The data suggest that S100A7/psoriasin-mediated regulation of the TJ barrier was via both the GSK-3 and MAPK pathways, as evidenced by the inhibitory effects of inhibitors for GSK-3 and MAPKs. CONCLUSIONS: Our finding that S100A7/psoriasin regulates differentiation and strengthens TJ barrier function provides novel evidence that, in addition to antimicrobial and immunoregulatory activities, S100A7/psoriasin is involved in skin innate immunity.