Cytokines and the skin barrier

Abstract

The skin is the largest organ of the human body and builds a barrier to protect us from the harmful environment and also from unregulated loss of water. Keratinocytes form the skin barrier by undergoing a highly complex differentiation process that involves changing their morphology and structural integrity, a process referred to as cornification. Alterations in the epidermal cornification process affect the formation of the skin barrier. Typically, this results in a disturbed barrier, which allows the entry of substances into the skin that are immunologically reactive. This contributes to and promotes inflammatory processes in the skin but also affects other organs. In many common skin diseases, including atopic dermatitis and psoriasis, a defect in the formation of the skin barrier is observed. In these diseases the cytokine composition within the skin is different compared to normal human skin. This is the result of resident skin cells that produce cytokines, but also because additional immune cells are recruited. Many of the cytokines found in defective skin are able to influence various processes of differentiation and cornification. Here we summarize the current knowledge on cytokines and their functions in healthy skin and their contributions to inflammatory skin diseases.

Figure 1

Schematic representation of the underlying differentiation process in keratinocytes. Keratinocytes differentiate from a proliferating state in the basal layer (Stratum basale) to dead corneocytes in the outermost layer (Stratum corneum). During this differentiation process the lipid envelope, the filaggrin/keratin network, and the cornified envelope is formed and desmosomes mature to corneodesmosomes. Together these components form a compact barrier against the outside preventing entry of harmful components, for example allergens, pathogens, irradiation and other irritants, into the skin and body. Furthermore the barrier inhibits the trans-epidermal water loss (TEWL) and associated loss of solutes. Dotted lines indicate where the sections in the scheme are localized in the normal human skin.

Figure 2

Cytokine receptor complexes, their ligand families and corresponding signaling pathways involved in skin barrier regulation. The cytokine receptor families are grouped according to the three-dimensional structure of the receptors. The receptors of the interleukin type I and interleukin type II families possess extracellular fibronectin like domains. These two families differ only in the WSXWS motif present in the type I, but not type II, receptors. The tumor necrosis factor receptor (TNFR) family has cysteine-rich motifs in their extracellular regions able to bind ligands. The immunoglobulin (Ig) superfamily shares extracellular regions structural homology with immunoglobulin domains.

Figure 3

Regulatory effects of the cytokines on the barrier formation. This figure illustrates the relevant effects of cytokines on the formation of the skin barrier and their selected targets in the differentiation process documented either in cell culture or in animal studies. Arrows indicate the consequences on these processes. (↑) indicate that the cytokine enhances or promotes the target process; (↓) indicate that the cytokine down-regulates or inhibits the target process.