Cytokinocytes: the diverse contribution of keratinocytes to immune responses in skin

Abstract

The skin serves as the primary interface between our body and the external environment and acts as a barrier against entry of physical agents, chemicals, and microbes. Keratinocytes make up the main cellular constitute of the outermost layer of the skin, contributing to the formation of the epidermis, and they are crucial for maintaining the integrity of this barrier. Beyond serving as a physical barrier component, keratinocytes actively participate in maintaining tissue homeostasis, shaping, amplifying, and regulating immune responses in skin. Keratinocytes act as sentinels, continuously monitoring changes in the environment, and, through microbial sensing, stretch, or other physical stimuli, can initiate a broad range of inflammatory responses via secretion of various cytokines, chemokines, and growth factors. This diverse function of keratinocytes contributes to the highly variable clinical manifestation of skin immune responses. In this Review, we highlight the highly diverse functions of epidermal keratinocytes and their contribution to various immune-mediated skin diseases.

Figure 1. Histology of the skin and the epidermis.

The epidermis is a dynamic tissue where keratinocytes exist in various stages of differentiation. Stem cells reside in the basal layer (stratum basale) of the epidermis and move through the subsequent layers with different progression of differentiation in the spinous layer (stratum spinosum), before expressing keratohyalin granules in the granular layer (stratum granulosum [SG]) and terminal differentiation in the stratum corneum (SC). Hematoxylin and eosin staining is shown in the image on the left (original magnification, ×200). Langerhans cells (LCs) reside within the epidermis as part of their surveillance function. In the stratum granulosum keratinocyte synthesis keratohyalin granules contain filaggrin monomers and lamellar granules contain lipids. Tight junctions are expressed in the granular layer. A pH gradient is maintained from the granular layer to the top of the stratum corneum, maintaining a pH of 4.5–5.3 at the surface of the skin. Adapted with permission from Journal of Clinical Investigation (158).

Figure 2. Expression of various cytokines and chemokines in keratinocytes.

The heatmap shows the induction of cytokines, chemokines, and various growth factors, via RNA sequencing, in human keratinocytes under various inflammatory conditions, including stimulation with IFN-α, IFN-γ, IL-13, IL-17A, TNF-α, IL-4, and IL-17A⁺ TNF-α. Keratinocytes have a dynamic response depending on the type of stimulation. The color gradient represents expression levels after normalization.

Figure 3. Diverse role of keratinocytes in inflammatory responses.

Keratinocytes express different microbial sensors and cytokine receptors, with highly variable expression in different layers of the epidermis. This likely accounts for type I IFN responses (antiviral) being most prominent in the basal layer of the epidermis but anti–IL-17 (antifungal) or antibacterial responses (as measured by expression of AMPs encoding genes) dominating in the top layer. In addition, keratinocytes express and secrete a variety of proinflammatory cytokines, including the IL-1 family members, IL20 family members, IL-12/IL-23 cytokines, type I IFN, IFN-κ, and various others. In addition, keratinocytes secrete a variety of growth factors that influence epidermis growth and differentiation, vascular growth, fibroblast proliferation, and nerves. The various chemokines secreted by keratinocytes drive influx of various types of inflammatory cell subsets depending on the chemokine signal.