Keratinocytes: innate immune cells in atopic dermatitis

Abstract

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.

Keywords: anti-microbial peptide; atopic dermatitis; chemokine; cytokine; innate immunity; keratinocyte.

Fig. 1

Basic epidermal structure and keratinocyte differentiation. During the process of epidermal differentiation, keratinocytes synthesize vital components that are necessary for the epidermal barrier function. The expression patterns of keratin intermediate filaments and transglutaminases correlate with the stage of epidermal differentiation. The intercellular adhesion complexes, including desmosomes and tight junction, provide strong mechanical attachments between adjacent keratinocytes. Cholesterol sulfate is formed in the viable epidermis by cholesterol sulfotransferase and desulfated in the intercorneocyte spaces by the enzyme steroid sulfatase, participating in the regulation of barrier homeostasis and desquamation. Lamellar bodies are secretory organelles containing lipids and enzymes that contribute to the formation of the intercorneocyte lipid lamellae. Keratohyalin granules are expressed in the stratum granulosum and contain profilaggrin, the precursor of filaggrin, which facilitates the aggregation of keratin filaments. Loricrin is a major component of the cornified cell envelope that is formed beneath the lipid bilayer cell membrane through the action of transglutaminase 1 (see inset).

Fig. 2

The contribution of keratinocyte‐derived mediators to the pathogenesis of atopic dermatitis. An impaired epidermal barrier in atopic dermatitis (AD) allows for the penetration of potential allergens, irritants and pathogens, such as Staphylococcus aureus, to initiate the immune activation of keratinocytes. Activated keratinocytes produce a plethora of proinflammatory cytokines and chemokines, including eotaxin/CC chemokine ligand (CCL) 11, eotaxin‐3/CCL26, monocyte chemotactic protein (MCP)‐4/CCL13, regulated on activation, normal T cell‐expressed and secreted (RANTES)/CCL5, and thymus and activation‐regulated chemokine (TARC)/CCL17, which attract and activate Langerhans cells (LCs), dendritic cells (DCs), eosinophils, basophils, mast cells, type‐2 innate lymphoid cells (ILC2) and T helper (Th) 17 cells. The cytokines released by these cells induce Th2 polarization, which plays a key role in the pathogenesis of AD. Keratinocytes also produce Th2‐promoting cytokines, including thymic stromal lymphopoietin (TSLP), interleukin (IL)‐25 and IL‐33, which further amplify the Th2 immune responses and exacerbate AD by inducing itching. TSLP, IL‐33 and Th2 cytokines (IL‐4, IL‐13 and IL‐31) inhibit the expression of skin‐derived host defense peptides (HDPs), and increased expression of IL‐22 up‐regulates HDP production in the chronic stages of AD. HDPs, including LL‐37, human β‐defensins (hBDs), S100A7 and RNase 7 improve the skin barrier integrity and promote anti‐microbial barrier function in AD skin. GM–CSF = granulocyte–macrophage colony‐stimulating factor; Ig = immunoglobulin; TNF = tumor necrosis factor.