Dysfunctional Skin-Derived Glucocorticoid Synthesis Is a Pathogenic Mechanism of Psoriasis

Hannen, Rosalind and Udeh-Momoh, Chinedu and Upton, James and Wright, Michael and Michael, Anthony and Gulati, Abha and Rajpopat, Shefali and Clayton, Nicky and Halsall, David and Burrin, Jacky and Flower, Roderick and Sevilla, Lisa and Latorre, Victor and Frame, James D. and Lightman, Stafford and Perez, Paloma and Philpott, Michael (2017) Dysfunctional Skin-Derived Glucocorticoid Synthesis Is a Pathogenic Mechanism of Psoriasis. Journal of Investigative Dermatology, 137 (8). pp. 1630-1637. ISSN 1523-1747

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Official URL: https://doi.org/10.1016/j.jid.2017.02.984

Abstract

Glucocorticoids (GC) are the primary steroids that regulate inflammation and have been exploited therapeutically in inflammatory skin diseases. Despite the broad-spectrum therapeutic use of GC, the biochemical rationale for locally treating inflammatory skin conditions is poorly understood, as systemic GC production remains largely functional in these patients. GC synthesis has been well characterized in healthy skin, but the pathological consequence has not been examined. Here we show de novo GC synthesis, and GC receptor expression is dysfunctional in both nonlesional and lesional psoriatic skin. Use of GC receptor epidermal knockout mice with adrenalectomy allowed for the distinction between local (keratinocyte) and systemic GC activity. Compensation exhibited by adult GC receptor epidermal knockout mice demonstrated that keratinocyte-derived GC synthesis protected skin from topical phorbol 12-myristate 13-acetate-induced inflammatory assault. Thus, localized de novo GC synthesis in skin is essential for controlling inflammation, and loss of the GC pathway in psoriatic skin represents an additional pathological process in this complex inflammatory skin disease.

Item Type: Journal Article
Faculty: ARCHIVED Faculty of Medical Science (until September 2018)
Depositing User: Ian Walker
Date Deposited: 25 Jun 2019 08:38
Last Modified: 14 Nov 2019 16:10
URI: http://arro.anglia.ac.uk/id/eprint/704465

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