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Keratinocyte glucocorticoids enable local immune resilience to preserve skin homeostasis.

ABSTRACT: Endogenous glucocorticoids (GCs) are pivotal in controlling inflammation. Keratinocyte-derived GCs contribute to local skin homeostasis as deletion of the GC-producing enzyme 11β-hydroxylase (Cyp11b1) in keratinocytes exacerbated skin inflammation. Since local tamoxifen-induced knockout (KO) induction may contribute to skin irritation, we implemented intraperitoneal injections to induce a systemic skin GC depletion preventing experimental skin irritation in order to reveal the importance of skin GC in steady-state. Both, local and systemic skin GC deficiency models exhibited reduced skin GC levels and increased migration of skin antigen-presenting cells to draining lymph nodes. However, systemic skin GC ablation did not result in pronounced skin inflammation as seen in local model. Interestingly, systemic skin GC deficiency elevated systemic inflammatory markers and provoked adrenal GC synthesis. RNA sequencing of keratinocytes revealed distinct gene expression patterns between local and systemic KOs. Local skin GC ablation showed a stronger inflammatory and apoptotic response, while systemic skin GC deficiency triggered several compensatory regulatory pathways, mitigating extensive skin inflammation. These findings underscore the critical role of local GCs in skin immune resilience against minor skin irritations and highlight the interplay between skin and adrenal GC levels.

ORGANISM(S): Mus musculus

PROVIDER: GSE271160 | GEO | 2024/08/01

REPOSITORIES: GEO

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Project description:Glucocorticoids (GCs) have a long history of use as therapeutic agents for numerous skin diseases. Surprisingly, their specific molecular effects are largely unknown. To characterize GC action in epidermis, we compared the transcriptional profiles of primary human keratinocytes untreated and treated with dexamethasone (DEX) for 1, 4, 24, 48 and 72 hours using large-scale microarray analyses. The majority of genes were found regulated only after 24 hours and remained regulated throughout the treatment. In addition to expected anti-inflammatory genes, we found that GCs regulate cell fate, tissue remodeling, cell motility, differentiation and metabolism. GCs not only effectively block signaling by TNF-alpha and IL-1 but also by IFN-gamma, which was not previously known. Specifically, GCs suppress the expression of essentially all IFN-gamma-regulated genes, including IFN-gamma receptor and STAT-1. GCs also block STAT-1 activation and nuclear translocation. Unexpectedly, GCs have anti-apoptotic effects in keratinocytes by inducing the expression of anti-apoptotic and repressing pro-apoptotic genes. Consequently, GCs treatment blocked UV-induced apoptosis of keratinocytes. GCs have a profound effect on wound healing by inhibiting cell motility and the expression of pro-angiogenic factor VEGF. They play an important role in tissue remodeling and scar formation by suppressing the expression of TGF-beta-1 and -2, MMP1, 2, 9 and 10 and inducing TIMP-2. Finally, GCs promote terminal stages of epidermal differentiation while simultaneously inhibiting the early stages. These results provide new insights into the beneficial and adverse effects of GCs in epidermis, defining the participating genes and mechanisms that coordinate the cellular responses important for GC-based therapies. Human epidermal keratinocytes are grown in delipidized, phenolphtalein-free medium and left as controls or treated with 0.1μM dexamethasone. Time course of treated and parallel control samples over a 72 hr period was performed twice with independent batches of cells.

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Keratinocyte glucocorticoids enable local immune resilience to preserve skin homeostasis.

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