An Inflamed and Infected Reconstructed Human Epidermis to Study Atopic Dermatitis and Skin Care Ingredients

Abstract

Atopic dermatitis (AD), the most common inflammatory skin disorder, is a multifactorial disease characterized by a genetic predisposition, epidermal barrier disruption, a strong T helper (Th) type 2 immune reaction to environmental antigens and an altered cutaneous microbiome. Microbial dysbiosis characterized by the prevalence of Staphylococcus aureus (S. aureus) has been shown to exacerbate AD. In recent years, in vitro models of AD have been developed, but none of them reproduce all of the pathophysiological features. To better mimic AD, we developed reconstructed human epidermis (RHE) exposed to a Th2 pro-inflammatory cytokine cocktail and S. aureus. This model well reproduced some of the vicious loops involved in AD, with alterations at the physical, microbial and immune levels. Our results strongly suggest that S. aureus acquired a higher virulence potential when the epidermis was challenged with inflammatory cytokines, thus later contributing to the chronic inflammatory status. Furthermore, a topical application of a Castanea sativa extract was shown to prevent the apparition of the AD-like phenotype. It increased filaggrin, claudin-1 and loricrin expressions and controlled S. aureus by impairing its biofilm formation, enzymatic activities and inflammatory potential.

Th2 Cytokines Affect the Innate Immune Barrier without Impairing the Physical Barrier in a 3D Model of Normal Human Skin

“…These data stand in continuation with the existing evidence obtained in in vitro keratinocytes [64,65] and strongly suggest that the alteration of the epidermal differentiation early occurs also in the presence of Th2 cytokines. Furthermore, the enlargement of intercellular spaces was evident as early as 24 h after Th2 cytokine incubation, in particular in the IL-13 group, suggesting that spongiosis is an initial AD pathogenetic event specifically triggered by Th2 cytokines, as recently reported [44][45][46].…”

“…We report that claudin-1 expression was not affected when either IL-4 or IL-13 alone was added, confirming the experimental evidence obtained in primary human keratinocytes by Yuki et al [43] and recently in reconstructed human epidermis by Cadau and Coll. [44]. Our study stands in continuation with in vitro studies [45] and Honzke's study performed in skin equivalents incubated with Th2 cytokines [46], with the evident advantage of displaying a fully developed epidermal barrier, thus allowing a more realistic and direct extrapolation to the clinics.…”

Skin barrier-inflammatory pathway is a driver of the psoriasis-atopic dermatitis transition

“…In AD, FLG gene mutations or expression defects ( 3 , 53 ) are considered a center factor in the “out-to-in” barrier pathogenesis observed in this condition ( 54 – 56 ). The resulting barrier defect gives rise to subsequent local and systemic Th2 immune responses, contributes to the early onset and persistence of AD ( 57 , 58 ), and manifests as symptoms such as dry skin ( 59 ), eczema, and asthma ( 60 , 61 ).…”

“…In psoriasis–AD overlap, the cytokines associated with Th1, Th17, and Th22 responses in psoriasis are beneficial to downregulating the expression of FLG , LOR, and IVL ( 41 – 48 ). This downregulation of FLG activates the Th2 immune axis ( 3 , 53 – 61 ), further exacerbating the inflammatory response. Additionally, the Th2 immune axis per se can also downregulate the expression of FLG , LOR, and IVL ( 42 ), which thus forms a feedback loop between the epidermal barrier and inflammatory factors.…”

From gut to skin: exploring the potential of natural products targeting microorganisms for atopic dermatitis treatment

“…124,125 Cytokines released in the microbial immune response can mediate the AD pruritic response by producing pruritic signals through the vagal or spinal nerve pathways. 126–128…”