Epidermal Inactivation of the Glucocorticoid Receptor Triggers Skin Barrier Defects and Cutaneous Inflammation
Open accessAbstract
The glucocorticoid (GC) receptor (GR) mediates the effects of physiological and pharmacological GC ligands and has a major role in cutaneous pathophysiology. To dissect the epithelial versus mesenchymal contribution of GR in developing and adult skin, we generated mice with keratinocyte-restricted GR inactivation (GR epidermal knockout or GR(EKO) mice). Developing and early postnatal GR(EKO) mice exhibited impaired epidermal barrier formation, abnormal keratinocyte differentiation, hyperproliferation, and stratum corneum (SC) fragility. At birth, GR(EKO) epidermis showed altered levels of epidermal differentiation complex genes, proteases and protease inhibitors which participate in SC maintenance, and innate immunity genes. Many upregulated genes, including S100a8/a9 and Tslp, also have increased expression in inflammatory skin diseases. Infiltration of macrophages and degranulating mast cells were observed in newborn GR(EKO) skin, hallmarks of atopic dermatitis. In addition to increased extracellular signal-regulated kinase activation, GR(EKO) newborn and adult epidermis had increased levels of phosphorylated signal transducer and activator of transcription 3, a feature of psoriasis. Although adult GR(EKO) epidermis had a mild phenotype of increased proliferation, perturbation of skin homeostasis with detergent or phorbol ester triggered an exaggerated proliferative and hyperkeratotic response relative to wild type. Together, our results show that epidermal loss of GR provokes skin barrier defects and cutaneous inflammation.
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Absence of glucocorticoid receptors in atopic dermatitis impairs skin permeability function.
“The absence of GRs in atopic dermatitis leads to impairment of skin permeability function [177].”
From Steroidogenesis in the skin: Implications for local immune functions (2013) · cites this paper as [177]
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Cites
Surjit, M., Ganti, K. P., Mukherji, A., Ye, T., Hua, G., Metzger, D., Li, M., & Chambon, P. (2011) · Cell · doi:10.1016/j.cell.2011.03.027 · Cited by 551 · cited 1× · see citing works
“…role in AD, indeed its overexpression in keratinocytes is sufficient to trigger an AD-like disease in mice (Li et al., 2005; Li et al., 2006; Zhang et al., 2009); importantly, Tslp levels in keratinocytes are transcriptionally repressed by ligand-activated GR (Li et al., 2006; Surjit et al., 2011).”
BackgroundMinireview: Latest Perspectives on Antiinflammatory Actions of Glucocorticoids
De Bosscher, K., & Haegeman, G. (2009) · Molecular Endocrinology · doi:10.1210/me.2008-0283 · Cited by 284 · see citing works
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Glucocorticoid receptor signaling in health and disease
Kadmiel, M., & Cidlowski, J. A. (2013) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2013.07.003 · Cited by 849 · see citing works
Steroidogenesis in the skin: Implications for local immune functions
Slominski, A., Zbytek, B., Nikolakis, G., Manna, P. R., Skobowiat, C., Zmijewski, M., Li, W., Janjetovic, Z., Postlethwaite, A., Zouboulis, C. C., et al. (2013) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2013.02.006 · Cited by 369 · see citing works
Association between Stress and the HPA Axis in the Atopic Dermatitis
Lin, T.-K., Zhong, L., & Santiago, J. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18102131 · Cited by 127 · see citing works
“Moreover, macrophage influx and mast cell degranulation have been observed in newborn GR (EKO) skin, both of which are hallmarks of AD [86].”
BackgroundSkin steroidogenesis in health and disease
Nikolakis, G., Stratakis, C. A., Kanaki, T., Slominski, A., & Zouboulis, C. C. (2016) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-016-9390-z · Cited by 76 · see citing works
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- Authors
- Sevilla, L. M., Latorre, V., Sanchis, A., & Pérez, P.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Corresponding author
- Pérez, Paloma
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 2013-02
- Volume
- 133
- Issue
- 2
- Pages
- 361-370
- ISSN
- 0022-202X (ISSN-L)
- OpenAlex
- W2006066882
- Cited by
- 77
- References
- 2
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 2 · 2023: 5 · 2022: 3 · 2021: 8 · 2020: 3 · 2019: 4 · 2018: 8 · 2017: 8 · 2016: 9 · 2015: 10 · 2014: 2 · 2013: 6 · 2012: 1
- FWCI
- 7.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, other-oa)
- Funders
- Generalitat Valenciana
- European Commission
- Ministerio de Ciencia e Innovación (ACOMP2011/127, BES-2009-021944)
- Topics
- Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Keywords
- glucocorticoid receptor, keratinocytes, skin barrier formation, keratinocyte differentiation, keratinocyte proliferation, epidermal differentiation complex, S100A8/A9, thymic stromal lymphopoietin, atopic dermatitis, psoriasis, mast cell degranulation, macrophage infiltration, ERK activation, STAT3 phosphorylation, skin homeostasis, hyperkeratosis
- MeSH terms
- Epidermal Cells, Animals, Animals, Newborn, Cell Differentiation, Dermatitis, Epidermis, Female, Genetic Markers, Male, Pregnancy, Receptors, Glucocorticoid, Skin Tests, Keratinocytes, Up-Regulation, Mice, Knockout, MAP Kinase Signaling System, Cell Proliferation, STAT3 Transcription Factor, Proto-Oncogene Proteins c-akt, Mice
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