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

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.

Cutaneous Glucocorticoidogenesis and Cortisol Signaling Are Defective in Psoriasis

“…These properties are also shared by CRH-related urocortins. The conclusion of the paper by Hannen et al (2017) that deficient GC signaling underlies the pathogenesis of psoriasis represents validation of the original theory concerning involvement of the HPA. That is, that defective attenuation of the CRH signaling system acting in concert with proinflammatory cytokines, and defective downstream immunosuppressive signaling composed of POMC peptides and GC, underlies the development and progression of inflammatory dermatoses, including psoriasis and autoimmune diseases, as had been proposed (Slominski, 2009; Slominski et al, 2013).…”

“…This would shield keratinocytes from the negative effects of enhanced cortisol levels, but protect UV-damaged epidermis from autoimmune attack by migrating immune cells that have an intact GR. A similar explanation was offered for enhanced protection of GC in GR epidermal knockout mouse skin against proinflammatory reactivity (Hannen et al, 2017). A possible role for hyperactivity of endogenous epidermal glucocorticosteroidogenesis in infection could be tested in impetiginized versus nonimpetiginized skin.…”

“…Glucocorticoid activity would be enhanced or counterbalanced by CRH, cytokines, urocortins, and POMC peptides. Taken together, the work by Hannen et al (2017) and the studies reviewed above offer guidance for alternative strategies in treating inflammatory dermatoses. For example, specific enzyme inhibitors could be used to regulate the enzymatic steps outlined in Figure 1b and c, or to inhibit enzymes that either esterify or degrade cortisol or corticosterone or to increase the intracellular NADPH/NADP + ratio favoring formation or reactivation of cortisol.…”

“…The investigative team led by Dr Hannen (Hannen et al, 2017) reports that synthesis of glucocorticoids (GC) and expression of nuclear GC receptors (GR) are inhibited in lesional and perilesional skin of patients with psoriasis. In a series of elegant experiments, they also provide proof that GC produced locally by epidermal keratinocytes protect the skin against inflammatory insults.…”

“…The locally produced pregnenolone undergoes further transformation to GC in all skin compartments, including the epidermis, dermis, hypodermis, and adnexal structures (Slominski et al, 2004, 2015a, 2015b). Interestingly, CYP11A1 protein expression was reduced in psoriatic skin and increased in the skin of adrenalectomized GR epidermal knockout mice (Hannen et al, 2017). These considerations indicate that CYP11A1 activity may play an important role in preventing or attenuating the presentation of psoriasis or other inflammatory skin disorders.…”