Updated Perspectives on Keratinocytes and Psoriasis: Keratinocytes are More Than Innocent Bystanders

Abstract

Psoriasis is a complex disease triggered by genetic, immunologic, and environmental stimuli. Many genes have been linked to psoriasis, like the psoriasis susceptibility genes, some of which are critical in keratinocyte biology and epidermal barrier function. Still, the exact pathogenesis of psoriasis is unknown. In the disease, the balance between the proliferative and differentiative processes of keratinocytes becomes altered. Multiple studies have highlighted the role of dysregulated immune cells in provoking the inflammatory responses seen in psoriasis. In addition to immune cells, accumulating evidence shows that keratinocytes are involved in psoriasis pathogenesis, as discussed in this review. Although certain immune cell-derived factors stimulate keratinocyte hyperproliferation, activated keratinocytes can also produce anti-microbial peptides, cytokines, and chemokines that can promote their proliferation, as well as recruit immune cells to help initiate and reinforce inflammatory feedback loops. Psoriatic keratinocytes also show intrinsic differences from normal keratinocytes even after removal from the in vivo inflammatory environment; thus, psoriatic keratinocytes have been found to exhibit abnormal calcium metabolism and possible epigenetic changes that contribute to psoriasis. The Koebner phenomenon, in which injury promotes the development of psoriatic lesions, also provides evidence for keratinocytes' contributions to disease pathogenesis. Furthermore, transgenic mouse studies have confirmed the importance of keratinocytes in the etiology of psoriasis. Finally, in addition to immune cells and keratinocytes, data in the literature support roles for other cell types, tissues, and systems in psoriasis development. These other contributors are all potential targets for therapies, suggesting the importance of a holistic approach when treating psoriasis.

Keywords: Koebner phenomenon; anti-microbial peptides; inflammation; innate immunity; skin.

Figure 1

The structure of the skin and the epidermis. Shown on the left is a schematic of normal human skin illustrating the three skin layers: the upper epidermis, the middle dermis, and the lower hypodermis. The schematic on the right is an amplified schematic of the epidermis showing the various strata/layers of the epidermis and some of the protein markers expressed in each stratum. The uppermost epidermal layer is the cornified layer (stratum corneum) consisting of essentially dead cells that help to provide a barrier function, followed by the granular layer (stratum granulosum) expressing filaggrin. The next deeper layer is the spinous layer (stratum spinosum) expressing involucrin more superficially as well as keratin (K)-1 (K1) and K10 more deeply, followed by the lowermost basal layer (stratum basale) expressing K5 and K14. Note that this schematic does not show the stratum lucidum or clear layer, which lies between the stratum corneum and stratum granulosum only in the thick skin of the palms and feet. Created using Biorender.com.

Figure 2

The structure of psoriatic skin with intrinsic differences between psoriatic and normal keratinocytes highlighted. On top is shown a schematic of psoriatic skin illustrating the scaly stratum corneum and the overall thickened epidermis, including elongated papillae and rete ridges with dilated capillaries in the dermis, as well as the immune cell infiltration and inflammation. In the inset, a keratinocyte from the basal layer of the epidermis is enlarged to illustrate intrinsic differences observed in psoriatic versus normal keratinocytes. The changes in psoriatic keratinocytes are indicated by the red arrows and include: abnormal calcium metabolism via decreased capacitative calcium influx [for example, decreased transient receptor potential canonical (TRPC) channel levels] and an increased cytosolic calcium response to ATP, as well as enhanced secretion of anti-microbial peptides, apparently upregulated at least in part as a result of epigenetic changes (e.g., hypomethylation of the S100A9 gene). All of these alterations in psoriatic keratinocytes amplify the inflammatory immune feedback loop that initiates and sustains chronic inflammation in psoriasis. Created using Biorender.com.