Inhibition of Keratinocyte Differentiation by the Synergistic Effect of IL-17A, IL-22, IL-1α, TNFα and Oncostatin M

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.

Oncostatin M overexpression induces skin inflammation but is not required in the mouse model of imiquimod‐induced psoriasis‐like inflammation

“…In previous studies, we described the proinflammatory role of OSM on human primary keratinocytes in vitro and its effects on epidermal differentiation using a 3D model of human reconstituted epidermis [14,20]. In the present study, we demonstrated that OSM is also a potent inductor of skin inflammation in the mouse system, leading to profound alterations of the epidermis structure.…”

“…In vitro, OSM induced the expression of antimicrobial peptides of the S100 family, chemokines (IL-8, CXCL5) and downregulated the expression of genes associated with keratinocyte differentiation such as cytokeratins (CKs)-10, involucrin, loricrin, or filaggrin [14]. OSM was also described as one of the five essential cytokines, with IL-1α, TNF-α, IL-17, and IL-22, acting in synergy to reproduce a psoriasislike phenotype on human primary keratinocytes [19], OSM being the most powerful cytokine in altering epidermal differentiation [20]. Among the gp130 cytokines, IL-6 was also reported to be overexpressed in psoriatic skin and to induce the proliferation of keratinocytes in vitro [21].…”

New Biological Activities of Lythrum salicaria L.: Effects on Keratinocytes, Reconstructed Epidermis and Reconstructed Skins, Applications in Dermo-Cosmetic Sciences

“…Mobile phases A and B were water with 0.1% formic acid and methanol with 0.1% formic acid, respectively. The separation was carried out at 30 • C with a gradient Normal human epidermal keratinocytes (NHEK) were obtained as previously described [15,16]. The cells were seeded in 96 well-plates and grown into confluence.…”

“…Reconstructed human epidermis (RHE) was generated on polycarbonate culture inserts, from surgical samples of pediatric foreskins, as previously described [15,16]. After shifting to air/liquid interface, RHE were cultured for seven days in the presence or not (control, no Vitamin C) of the Lythrum salicaria extract (concentrations indicated in the legends of the figures) or of Vitamin C. RHE treatments were renewed every two or three days.…”

“…RHE were processed, as previously described [15]. Briefly, at the end of incubation they were fixed with formaldehyde and fixed tissues were dehydrated with increasing ethanol concentrations, embedded in paraffin, and sections were carried out using a microtome (thickness of 5 µm).…”