Abstract
Keratinocyte differentiation program leading to an organized epidermis plays a key role in maintaining the first line of defense of the skin. Epidermal integrity is regulated by a tight communication between keratinocytes and leucocytes, particularly under cytokine control. Imbalance of the cytokine network leads to inflammatory diseases such as psoriasis. Our attempt to model skin inflammation showed that the combination of IL-17A, IL-22, IL-1α, OSM and TNFα (Mix M5) synergistically increases chemokine and antimicrobial-peptide expression, recapitulating some features of psoriasis. Other characteristics of psoriasis are acanthosis and down-regulation of keratinocyte differentiation markers. Our aim was to characterize the specific roles of these cytokines on keratinocyte differentiation, and to compare with psoriatic lesion features. All cytokines decrease keratinocyte differentiation markers, but IL-22 and OSM were the most powerful, and the M5 strongly synergized the effects. In addition, IL-22 and OSM induced epidermal hyperplasia in vitro and M5 induced epidermal thickening and decreased differentiation marker expression in a mouse model, as observed in human psoriatic skin lesions. This study highlights the precise role of cytokines in the skin inflammatory response. IL-22 and OSM more specifically drive epidermal hyperplasia and differentiation loss while IL-1α, IL-17A and TNFα were more involved in the activation of innate immunity.
Highlights
The skin is the largest barrier against various physical, chemical or biological stresses, constituting the first line of defense of the body
Since skin inflammation is associated with epidermal hyperplasia, we further asked for such a synergy in keratinocyte differentiation inhibition associated with acanthosis
A strong synergy of the mix of 5 cytokines (M5) cytokine combination was observed for desmoglein 1 (DSG1), calmodulin-like skin protein (CLSP) and FLG mRNA inhibition, whereas only an additive effect of the cytokines was seen for LOR, desmocollin 1 (DSC1), cytokeratin 1 (CK1) and fatty acid binding protein 5 (FABP5) (Figure 1A)
Summary
The skin is the largest barrier against various physical, chemical or biological stresses, constituting the first line of defense of the body. Due to a number of known or lesser known reasons (genetic or environmental factors,...), an inadequate response could generate a cytokine-mediated vicious circle, promoting a chronic inflammation, such as in psoriasis [2] In this context, keratinocytes are direct targets for numerous cytokines, leading to the regulation of their biological properties contributing to the inflammatory response such as the secretion of cytokines, chemokines and antimicrobial peptides, their differentiation and migration capacities. A complex cytokine network has been described in psoriasis and highlighted a central role of proinflammatory cytokines such as IL-23, IL-22, IL17, IL-1 or TNFa produced by infiltrated immune cells [2,3,4,5,6] Cytokine combinations such as IL-17A and IFNc, IL-17A and TNFa or IL-17A and IL-22 result in a synergistic effect on chemokine and antimicrobial peptide production [7,8,9]. We showed that the association of IL-1a, IL-17A, IL-22, OSM and TNFa exhibits a very strong synergy on keratinocytes by increasing the expression of inflammatory/innate immunity related molecules such as chemokines and antimicrobial peptides, generating an in vitro model of skin inflammation mimicking features of psoriasis [10,11]
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