A Tissue-Engineered Human Psoriatic Skin Model to Investigate the Implication of cAMP in Psoriasis: Differential Impacts of Cholera Toxin and Isoproterenol on cAMP Levels of the Epidermis.

Mélissa Simard,Sophie Morin,Rachelle Séguin,Roxane Pouliot,Geneviève Rioux,Estelle Loing

doi:10.3390/ijms21155215

Mélissa Simard, Sophie Morin + Show 4 more

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https://doi.org/10.3390/ijms21155215

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Abstract

Pathological and healthy skin models were reconstructed using similar culture conditions according to well-known tissue engineering protocols. For both models, cyclic nucleotide enhancers were used as additives to promote keratinocytes’ proliferation. Cholera toxin (CT) and isoproterenol (ISO), a beta-adrenergic agonist, are the most common cAMP stimulators recommended for cell culture. The aim of this study was to evaluate the impact of either CT or ISO on the pathological characteristics of the dermatosis while producing a psoriatic skin model. Healthy and psoriatic skin substitutes were produced according to the self-assembly method of tissue engineering, using culture media supplemented with either CT (10−10 M) or ISO (10−6 M). Psoriatic substitutes produced with CT exhibited a more pronounced psoriatic phenotype than those produced with ISO. Indeed, the psoriatic substitutes produced with CT had the thickest epidermis, as well as contained the most proliferating cells and the most altered expression of involucrin, filaggrin, and keratin 10. Of the four conditions under study, psoriatic substitutes produced with CT had the highest levels of cAMP and enhanced expression of adenylate cyclase 9. Taken together, these results suggest that high levels of cAMP are linked to a stronger psoriatic phenotype.

Highlights

Psoriasis is an autoimmune skin disease affecting 3% of the population worldwide and for which no cure currently exists [1]
These results show that higher cAMP levels would be associated with a stronger psoriatic phenotype, such as epidermal hyperproliferation and altered epidermal differentiation, supporting studies in which cAMP levels are found to be increased in psoriatic skin
In the presence of healthy keratinocytes, both cAMP enhancers (CT and ISO) stimulate the production of cAMP in the same manner, the concentration of Cholera toxin (CT) used in the experiment was lower than the concentration of ISO

Summary

Introduction

Psoriasis is an autoimmune skin disease affecting 3% of the population worldwide and for which no cure currently exists [1]. Clinical manifestation of psoriasis is defined by the apparition of red plaques with white scales, which have detrimental consequences on patient’s quality of life [2,3]. The histological hallmarks of psoriasis are a marked thickening of the epidermis, due to keratinocyte hyperproliferation, abnormal epidermal differentiation, and immune keratinocytes activation accompanied with immune cell infiltrate [4]. The granular layer of the epidermis is reduced in thickness and the horny layer contains some undifferentiated keratinocytes, which still contain cell nuclei [5]. Altered keratinocyte differentiation in psoriasis results at a molecular level in the deregulation of the epidermal differentiation marker proteins, such as involucrin (up-regulated), filaggrin (down-regulated), and keratin 10 (down-regulated) [6,7,8]. The exact cause of psoriasis is still unknown, making it difficult to develop an effective treatment for the pathology [1]

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