Identification of Keratinocyte Mitogens: Implications for Hyperproliferation in Psoriasis and Atopic Dermatitis

Abstract

Psoriasis and atopic dermatitis are chronic inflammatory skin diseases characterized by keratinocyte (KC) hyperproliferation and epidermal acanthosis (hyperplasia). The milieu of disease-associated cytokines and soluble factors is considered a mitogenic factor; however, pinpointing the exact mitogens in this complex microenvironment is challenging. We employed organotypic human epidermal equivalents, faithfully mimicking native epidermal proliferation and stratification, to evaluate the proliferative effects of a broad panel of (literature-based) potential mitogens. The KC GF molecule, the T-helper 2 cytokines IL-4 and IL-13, and the psoriasis-associated cytokine IL-17A caused acanthosis by hyperplasia through a doubling in the number of proliferating KCs. In contrast, IFN-γ lowered proliferation, whereas IL-6, IL-20, IL-22, and oncostatin M induced acanthosis not by hyperproliferation but by hypertrophy. The T-helper 2‒cytokine‒mediated hyperproliferation was Jak/signal transducer and activator of transcription 3 dependent, whereas IL-17A and KC GF induced MAPK/extracellular signal‒regulated kinase kinase/extracellular signal‒regulated kinase‒dependent proliferation. This discovery that key regulators in atopic dermatitis and psoriasis are direct KC mitogens not only adds evidence to their crucial role in the pathophysiological processes but also highlights an additional therapeutic pillar for the mode of action of targeting biologicals (e.g., dupilumab) or small-molecule drugs (e.g., tofacitinib) by the normalization of KC turnover within the epidermal compartment.

Polyunsaturated Fatty Acid-Derived Lipid Mediators That Regulate Epithelial Homeostasis

“…Dysfunction of epithelial layer is involved in various disorders, such as inflammatory and allergic diseases. [7][8][9][10][11][12][13][14][15][16] Thus, chemical mediators and their receptors that orchestrate epithelial homeostasis have received great attention as potential therapeutic targets for epithelial diseases.…”

Electrical Impedance Spectroscopy Quantifies Skin Barrier Function in Organotypic In Vitro Epidermis Models

“…After examining EIS in epidermal homeostasis we aimed to study the relevance of EIS in the context of disturbed homeostasis and to deepen our investigation into the correlation between EIS diff , epidermal thickness and terminal differentiation. Therefore, HEEs from normal human keratinocytes (NHEKs) were stimulated with single cytokines (interleukin–(IL–) 17A or IL–22) or cytokine mixes (IL–17A + IL–22 and IL–4 + IL–13) to mimic a pro–inflammatory milieu that is known to affect keratinocyte proliferation (IL–4, IL–13, IL–17A), the cell volume (IL–22), and terminal differentiation (all cytokines) (Niehues et al . 2021) (Figure 4a).…”

Ghrelin Represses Thymic Stromal Lymphopoietin Gene Expression through Activation of Glucocorticoid Receptor and Protein Kinase C Delta in Inflamed Skin Keratinocytes

“…Epidermal hyperplasia is a histological hallmark promoted by various growth factors and cytokines such as keratinocyte growth factor (KGF), IL-4, IL-13, IL-17A, IL-22, and IL-24 in AD [ 103 , 104 ]. We found that ghrelin suppresses epidermal hyperplasia probably due to inhibition of expression of IL-4, IL-13, and IL-22 genes by ghrelin in DNFB-induced AD-like mouse skin, implying anti-proliferation activity of ghrelin ( Supplementary Figure S1 ).…”