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• W2598859771 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. 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. Psoriasis affects 2% of the world’s population, of which 80% suffer from mild forms of the disease that are commonly treated with topical therapies (Uva et al., 2012Uva L. Miguel D. Pinheiro C. Antunes J. Cruz D. Ferreira J. et al.Mechanisms of action of topical corticosteroids in psoriasis.Int J Endocrinol. 2012; 2012: 561018Crossref PubMed Scopus (115) Google Scholar). Glucocorticoids (GC), often in combination with vitamin D or retinoids, are the primary topical therapeutics for mild-moderate psoriasis. GC, released as cortisol (humans) and corticosterone (rodents), are stress-response hormones with potent immunoregulatory mechanisms (Lightman et al., 2008Lightman S.L. Wiles C.C. Atkinson H.C. Henley D.E. Russell G.M. Leendertz J.A. et al.The significance of glucocorticoid pulsatility.Eur J Pharmacol. 2008; 583: 255-262Crossref PubMed Scopus (174) Google Scholar). GC can suppress keratinocyte inflammation, downregulate proliferation, and promote differentiation (Stojadinovic et al., 2006Stojadinovic O. Lee B. Vouthounis C. Vukelic S. Pastar I. Blumenberg M. et al.Novel genomic effects of glucocorticoids in epidermal keratinocytes: inhibition of apoptosis, interferon-gamma pathway, and wound healing along with promotion of terminal differentiation.J Biol Chem. 2006; 282: 4021-4034Crossref PubMed Scopus (154) Google Scholar). Because GC form an integral component of many topical psoriasis therapies, and healthy keratinocytes can synthesize GC de novo (Cirillo and Prime, 2011Cirillo N. Prime S.S. Keratinocytes synthesize and activate cortisol.J Cell Biochem. 2011; 112: 1499-1505Crossref PubMed Scopus (84) Google Scholar, Hannen et al., 2011Hannen R.F. Michael A.E. Jaulim A. Bhogal R. Burrin M. Philott M.P. Steroid synthesis by primary human keratinocytes; implications for skin disease.Biochem Biophys Res Commun. 2011; 404: 62-67Crossref PubMed Scopus (64) Google Scholar, Vukelic et al., 2011Vukelic S. Stojadinovic O. Pastar I. Rabach M. Krzyzanowska A. Lebrun E. et al.Cortisol synthesis in epidermis is induced by IL-1 and tissue injury.J Biol Chem. 2011; 286: 10265-10275Crossref PubMed Scopus (148) Google Scholar, Wierzbicka et al., 2016Wierzbicka J.M. Żmijewski M.A.A. Antoniewicz J. Sobjanek M. Slominski A.T. Differentiation of keratinocytes modulates skin HPA analog.J Cell Physiol. 2016; 232: 154-166Crossref PubMed Scopus (17) Google Scholar), we hypothesize that loss of effective skin-GC synthesis would form a pathogenic mechanism of psoriasis. Systemically, GC are produced via the hypothalamic-pituitary-adrenal (HPA) axis, forming an integral circadian rhythm and acutely in response to stress. In psoriasis, the systemic HPA axis remains largely unperturbed (Karanikas et al., 2009Karanikas E. Harsoulis F. Giouzepas I. Griveas I. Chrisomallis F. Neuroendocrine stimulatory tests of hypothalamus-pituitary-adrenal axis in psoriasis and correlative implications with psychopathological and immune parameters.J Dermatol. 2009; 36: 35-44Crossref PubMed Scopus (21) Google Scholar) and patients with psoriasis are not routinely prescribed systemic GC treatment. Healthy skin has a localized HPA axis, expressing all the components for regulating and synthesizing GC (Ito et al., 2005Ito N. Ito T. Kromminga A. Bettermann A. Takigawa M. Kees F. et al.Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize cortisol.FASEB J. 2005; 19: 1332-1334Crossref PubMed Scopus (407) Google Scholar, Jozic et al., 2015Jozic I. Stojadinovic O. Kirsner R.S. Tomic-Canic M. Skin under the (spot)-light: cross-talk with the central hypothalamic-pituitary-adrenal (HPA) axis.J Invest Dermatol. 2015; 135: 1469-1471Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, Slominski et al., 2007Slominski A. Wortsman J. Tuckey R.C. Paus R. Differential expression of HPA axis homolog in the skin.Mol Cell Endocrinol. 2007; 265-266: 143-149Crossref PubMed Scopus (214) Google Scholar, Slominski et al., 2014Slominski A.T. Manna P.R. Tuckey R.C. Cutaneous glucocorticosteroidogenesis: securing local homeostasis and the skin integrity.Exp Dermatol. 2014; 23: 369-374Crossref PubMed Scopus (56) Google Scholar, Slominski et al., 2015Slominski A.T. Manna P.R. Tuckey R.C. On the role of skin in the regulation of local and systemic steroidogenic activities.Steroids. 2015; 103: 72-88Crossref PubMed Scopus (124) Google Scholar, Skobowiat et al., 2011Skobowiat C. Dowdy J.C. Sayre R.M. Tuckey R.C. Slominski A. Cutaneous hypothalamic-pituitary-adrenal axis homolog: regulation by ultraviolet radiation.Am J Physiol Endocrinol Metab. 2011; 301: E484-E493Crossref PubMed Scopus (150) Google Scholar, Skobowiat and Slominski, 2015Skobowiat C. Slominski A. UVB activates hypothalamic-pituitary-adrenal axis in C57BL/6 mice.J Invest Dermatol. 2015; 135: 1638-1648Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, Wierzbicka et al., 2016Wierzbicka J.M. Żmijewski M.A.A. Antoniewicz J. Sobjanek M. Slominski A.T. Differentiation of keratinocytes modulates skin HPA analog.J Cell Physiol. 2016; 232: 154-166Crossref PubMed Scopus (17) Google Scholar, Zmijewski et al., 2007Zmijewski M.A. Sharma R.K. Slominski A.T. Expression of molecular equivalent of hypothalamic-pituitary-adrenal axis in adult retinal pigment epithelium.J Endocrinol. 2007; 193: 1-157Crossref PubMed Scopus (36) Google Scholar); however, the rate of GC synthesis is <1% of classic steroidogenic tissue (Slominski et al., 2004Slominski A. Zjawiony J. Wortsman J. Semak I. Stewart J. Pisarchik A. et al.A novel pathway for sequential transformation of 7-dehydrocholesterol and expression of the P450scc system in mammalian skin.Eur J Biochem. 2004; 271: 4178-4188Crossref PubMed Scopus (204) Google Scholar, Slominski et al., 2015Slominski A.T. Manna P.R. Tuckey R.C. On the role of skin in the regulation of local and systemic steroidogenic activities.Steroids. 2015; 103: 72-88Crossref PubMed Scopus (124) Google Scholar). Thus the significance relative to the abundant systemic supply from adrenal glands remains contested (Jozic et al., 2015Jozic I. Stojadinovic O. Kirsner R.S. Tomic-Canic M. Skin under the (spot)-light: cross-talk with the central hypothalamic-pituitary-adrenal (HPA) axis.J Invest Dermatol. 2015; 135: 1469-1471Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). Psoriasis is primarily considered an immune condition, but precisely why the immune system targets skin in psoriasis and is activated after environmental stress is unclear. The skin-HPA axis has been suggested as a stress-response mechanism (Reich et al., 2010Reich A. Wójcik-Maciejewicz A. Slominski A.T. Stress and the skin.G Ital Dermatol Venereol. 2010; 145: 213-219PubMed Google Scholar, Slominski et al., 2013aSlominski A. Zbytek B. Nikolakis G. Manna P.R. Skobowiat C. Zmijewski M. et al.Steroidogenesis in the skin: implications for local immune functions.J Steroid Biochem Mol Biol. 2013; 137: 107-123Crossref PubMed Scopus (257) Google Scholar, Slominski et al., 2013bSlominski A.T. Zmijewski M.A. Zbytek B. Tobin D.J. Theoharides T.C. Rivier J. Key role of CRF in the skin stress response system.Endocr Rev. 2013; 34: 827-884Crossref PubMed Scopus (281) Google Scholar), and healthy human keratinocytes respond to stressors such as humidity (Takei et al., 2013Takei K. Denda S. Kumamoto J. Denda M. Low environmental humidity induces synthesis and release of cortisol in an epidermal organotypic culture system.Exp Dermatol. 2013; 22: 662-664Crossref PubMed Scopus (21) Google Scholar), UV light (Skobowiat and Slominski, 2015Skobowiat C. Slominski A. UVB activates hypothalamic-pituitary-adrenal axis in C57BL/6 mice.J Invest Dermatol. 2015; 135: 1638-1648Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar), and trauma (Vukelic et al., 2011Vukelic S. Stojadinovic O. Pastar I. Rabach M. Krzyzanowska A. Lebrun E. et al.Cortisol synthesis in epidermis is induced by IL-1 and tissue injury.J Biol Chem. 2011; 286: 10265-10275Crossref PubMed Scopus (148) Google Scholar) by de novo synthesizing GC. Thus defective GC synthesis in psoriasis skin could form an additional mechanism to explain uncontrolled inflammation within lesional tissue and heightened sensitivity to disease flare from environmental cues. Here we assess the necessity of localized GC synthesis in skin independently of the adrenal gland, and its pathological consequences in psoriasis. RNA relative expression analysis of enzymes required for de novo cortisol synthesis was analyzed from Nair et al., 2009Nair R.P. Duffin K.C. Helms C. Ding J. Stuart P.E. Goldgar D. et al.Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.Nat Genet. 2009; 41: 199-204Crossref PubMed Scopus (1068) Google Scholar using the NCBI GEO profiling database (http://www.ncbi.nlm.nih.gov/geo/) and revealed decreased StAR and 3βHSD1 (P < 0.0001) in psoriasis skin (Figure 1a). We previously reported an absence of StAR expression in psoriatic skin (Hannen et al., 2011Hannen R.F. Michael A.E. Jaulim A. Bhogal R. Burrin M. Philott M.P. Steroid synthesis by primary human keratinocytes; implications for skin disease.Biochem Biophys Res Commun. 2011; 404: 62-67Crossref PubMed Scopus (64) Google Scholar), but we show here that 3βHSD1 protein was absent in nonlesional and lesional psoriatic epidermis. In addition, CYP11A1 and CYP17 proteins were significantly reduced in lesional psoriatic skin, although there was a small increase in CYP11A1 RNA expression in the psoriatic lesion (Figure 1b). Gene expression of 11βHSD1 and 11βHSD2, responsible for cortisol to cortisone interconversion, was also significantly reduced in lesional tissue (Figure 1a). De novo cortisol synthesis in primary healthy and psoriatic keratinocytes was assessed by [3H]-pregnenolone radiometric assay (Figure 1c). More than 40% [3H]-pregnenolone was metabolized to cortisol in healthy primary keratinocytes, confirmed by comigration with an authentic [1,2,6,7-3H]-cortisol standard. Less than 10% of pregnenolone was metabolized to cortisol in uninvolved and involved psoriatic keratinocytes (Figure 1d). There was little metabolism of [3H]-pregnenolone in involved keratinocytes. In uninvolved psoriatic keratinocytes, metabolic intermediates were still detected together with increased formation of highly polar steroid species correlating with sulfated steroids (Figure 1c and Supplementary Figure S1 online). Steroid sulfotransferase SULT2B1 was significantly elevated in uninvolved and involved psoriasis skin relative to healthy controls (Supplementary Figure S1). Sulfate conjugation is an excretion mechanism for steroid clearance (Mueller et al., 2015Mueller J.W. Gilligan L.C. Idkowiak J. Arlt W. Foster P.A. The regulation of steroid action by sulfation and desulfation.Endocr Rev. 2015; 36: 526-563Crossref PubMed Scopus (250) Google Scholar) and could account for the depletion of cortisol bioavailability in uninvolved psoriasis skin. Cortisol secretion by whole-skin mounts, from normal and paired uninvolved and involved psoriatic skin, was assessed by liquid chromatography-tandem mass spectrometry. Cortisol secretion was decreased by >90% in uninvolved and involved lesional psoriasis skin compared with healthy skin (healthy skin 809.6 ± 120.4 ng/ml; uninvolved 63.1 ± 7.9 ng/ml; involved 67.7 ± 11.8 ng/ml psoriatic skin; P < 0.01, n = 8) (Figure 1e). Cortisone levels were also significantly (P < 0.001) lower in psoriatic tissue (normal skin 1,940.0 ± 436.3 ng/ml, uninvolved 272.5 ± 211.5 ng/ml; involved 320.6 ± 101.4 ng/ml psoriatic skin) (Figure 1f), indicating that decreased cortisol levels did not occur via shifts in 11βHSD1 shuttle activity. If changes in the direction of 11βHSD1 activity were responsible for depleted cortisol levels, a concomitant increase in cortisone levels would be expected, which was not observed here. The cortisol to cortisone ratio was still 1:2 respectively in both normal and psoriatic systems. Instead, these data suggest that decreased de novo synthesis with steroid sulfation is responsible for dramatic cortisol reduction in psoriatic keratinocytes. We assessed glucocorticoid receptor (GR) and active (GC/ligand-bound) phospho-Ser211 GRα (pGR) to determine whether decreased local cortisol production was associated with decreased GR phosphorylation. Relative expression analysis identified a significant reduction of GR in lesional psoriatic skin compared with healthy controls and nonlesional skin (Figure 2a). However, immunoblotting and immunofluorescence histochemistry showed that there was a significant (P < 0.05) downregulation of pGR and GR expression in uninvolved psoriatic skin (Figure 2). GR was undetectable in 18 of the 20 involved psoriatic skin biopsies by immunofluorescence histochemistry and was significantly (P < 0.05) reduced in immunoblotting analysis (Figure 2). Notably, there was no difference between uninvolved and healthy skin at the mRNA level; thus a reduction of GR protein expression in uninvolved tissue is either due to changes of translation or degradation. Because GR expression is essential for epidermal barrier integrity, reduced expression of GR in psoriatic skin could directly affect barrier function. To examine the specific importance of local keratinocyte cortisol synthesis and associated GR response, we utilized keratinocyte GR knockout mice (GREKO; K5-cre//GRloxP/loxP). Multiple keratinocyte steroid enzyme knockouts would be required to achieve the same effect as knocking out the GR to locate the GC-specific response; thus the GREKO mouse was more suitable for this initial study. To separate local from systemic GR responses, control (CON; 0cre//GRloxP/loxP) and GREKO mice were adrenalectomized (ADX) or sham operated (Sham), to create four groups: (i) CON-Sham; (ii) CON-ADX; (iii) GREKO-Sham; (iv) GREKO-ADX. Mice were topically administered phorbol 12-myristate 13-acetate (PMA) (8 μg) to one side of the dorsal skin to examine differences in inflammation. In the absence of PMA, there was little phenotypic difference and no difference in epidermal thickness in adult (week 15) CON and GREKO mouse skin, regardless of ADX (Figure 3a). In the presence of PMA, male adult CON-Sham and CON-ADX epidermis was severely disrupted with epidermal thickening and immune cell infiltration (Figure 3a); 50% of CON-Sham and 60% of CON-ADX mice exhibited regions of complete epidermal destruction. In comparison, GREKO-Sham showed no significant epidermal thickening relative to untreated controls and only one GREKO-ADX mouse exhibited increased skin thickness, depicted in the scatter plot distribution (Figure 3b). Epidermal destruction was not detected in GREKO-Sham and was only observed in 25% GREKO-ADX mice (Figure 3b). Inflammatory profiles of male CON PMA-treated dorsal skin showed induction of IL-1β, IL-6, tumor necrosis factor-α, and monocyte chemotactic protein-1 mRNA levels (Figure 3c). In particular, PMA elevated IL-1β 30-fold in CON-Sham and 70-fold in CON-ADX male animals, whereas GREKO-Sham and GREKO-ADX mice were protected from PMA-mediated inflammation. Unlike male CON-Sham mice, the inflammatory profile of female CON-Sham mice was not elevated on PMA application, although the skin did appear hyperproliferative (Supplementary Figure S2 online). PMA increased epidermal thickness in all groups, but no complete epidermal destruction was observed in any of the female groups. However, two of three female CON-ADX animals died within 12 hours of PMA application and the inflammatory profile of the surviving female mouse measured IL-1β 60-fold higher (Supplementary Figure S2). In contrast, all the female GREKO-ADX animals survived, did not exhibit excessive IL-1β induction, and were protected from immune cell infiltration. A similar profile was detected with tumor necrosis factor-α, which was 8-fold higher in PMA CON-ADX female mice. Therefore, some sexual dichotomy was observed, although female adult GREKO mice still exhibited protection from PMA-induced inflammation since they survived the duration of the experiment. The protective effects observed in adult GREKO mice were surprising because we hypothesized that mice lacking keratinocyte GR would have an overactive inflammatory response. To understand mechanisms underlying the protective inflammatory phenotype in adult GREKO mice, we assessed systemic and skin corticosterone (CORT) levels. Adult GREKO mice displayed a normal AM-PM circadian rhythm (Figure 4a), a critical process for normal systemic CORT regulation and secretion. CORT levels were markedly reduced in CON-ADX mice, an effect that was maintained 7 days after ADX, demonstrating the effectiveness of the procedure (Figure 4b). In contrast to CON-ADX, GREKO-ADX mice displayed similar levels of CORT to Sham mice (Figure 4b). liquid chromatography-tandem mass spectrometry analysis revealed elevated CORT levels in the skin of adult GREKO-Sham mice relative to CON-Sham mice (Figure 4c and Supplementary Figure S3). Although CORT levels were significantly reduced in CON-ADX mice as expected, there were still measurable amounts of CORT in the skin. Whole skin CORT levels in GREKO-ADX animals were three-fold higher compared with CON-ADX mice and were not significantly different from CON-Sham mice. This demonstrates a measurable amount of CORT in skin from a nonadrenal source. Key regulators of the HPA axis (CRH and POMC mRNA and CYP11A1 protein) were significantly elevated in GREKO compared with CON mouse skin (Figure 4d–f). Hence, although GR was knocked out in GREKO epidermis, skin synthesis of CORT was not compromised and was elevated to compensate for the loss of GR in keratinocytes. The compensatory local GC supply in adult GREKO mice was sufficient to protect the skin from PMA-induced immune cell infiltration (that express GR) through paracrine signaling, even in the absence of the adrenal glands. Thus, local CORT can have a physiological influence on keratinocyte/epidermal function that is distinct from systemic CORT. These data demonstrate that local de novo GC synthesis is present and adaptable in skin to protect from inflammation. Because the GC pathway is severely compromised in psoriatic skin, the loss of this pathway could contribute to the exacerbated inflammatory response observed in psoriasis. GC are powerful anti-inflammatory compounds and are the primary therapeutic for the majority of inflammatory skin conditions (Rahman et al., 2012Rahman M. Alam K. Ahmad M.Z. Gupta G. Afzal M. Akhter S. et al.Classical to current approach for treatment of psoriasis: a review.Endocr Metab Immune Disord Drug Targets. 2012; 12: 287-302Crossref PubMed Scopus (85) Google Scholar). Although de novo GC synthesis has been well researched in healthy skin (Cirillo and Prime, 2011Cirillo N. Prime S.S. Keratinocytes synthesize and activate cortisol.J Cell Biochem. 2011; 112: 1499-1505Crossref PubMed Scopus (84) Google Scholar, Hannen et al., 2011Hannen R.F. Michael A.E. Jaulim A. Bhogal R. Burrin M. Philott M.P. Steroid synthesis by primary human keratinocytes; implications for skin disease.Biochem Biophys Res Commun. 2011; 404: 62-67Crossref PubMed Scopus (64) Google Scholar, Ito et al., 2005Ito N. Ito T. Kromminga A. Bettermann A. Takigawa M. Kees F. et al.Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize cortisol.FASEB J. 2005; 19: 1332-1334Crossref PubMed Scopus (407) Google Scholar, Skobowiat et al., 2011Skobowiat C. Dowdy J.C. Sayre R.M. Tuckey R.C. Slominski A. Cutaneous hypothalamic-pituitary-adrenal axis homolog: regulation by ultraviolet radiation.Am J Physiol Endocrinol Metab. 2011; 301: E484-E493Crossref PubMed Scopus (150) Google Scholar, Slominski et al., 1996Slominski A. Ermak G. Mihm M. ACTH receptor, CYP11A1, CYP17 and CYP21A2 genes are expressed in skin.J Clin Endocrinol Metab. 1996; 81: 2746-2749Crossref PubMed Scopus (192) Google Scholar, Slominski et al., 2005aSlominski A. Zbytek B. Semak I. Sweatman T. Wortsman J. CRH stimulates POMC activity and corticosterone production in dermal fibroblasts.J Neuroimmunol. 2005; 162: 97-102Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, Slominski et al., 2005bSlominski A. Zbytek B. Szczesniewski A. Semak I. Kaminski J. Sweatman T. et al.CRH stimulation of corticosteroids production in melanocytes is mediated by ACTH.Am J Physiol Endocrinol Metab. 2005; 288: E701-E706Crossref PubMed Scopus (174) Google Scholar, Slominski et al., 2006Slominski A. Zbytek B. Szczesniewski A. Wortsman J. Cultured human dermal fibroblasts do produce cortisol.J Invest Dermatol. 2006; 126: 1177-1178Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, Slominski et al., 2012Slominski A.T. Zmijewski M.A. Skobowiat C. Zbytek B. Slominski R.M. Steketee J.D. Sensing the environment: regulation of local and global homeostasis by the skin’s neuroendocrine system.Adv Anat Embryol Cell Biol. 2012; 212 (v, vii, 1–115)Crossref PubMed Scopus (473) Google Scholar, Slominski et al., 2014Slominski A.T. Manna P.R. Tuckey R.C. Cutaneous glucocorticosteroidogenesis: securing local homeostasis and the skin integrity.Exp Dermatol. 2014; 23: 369-374Crossref PubMed Scopus (56) Google Scholar, Vukelic et al., 2011Vukelic S. Stojadinovic O. Pastar I. Rabach M. Krzyzanowska A. Lebrun E. et al.Cortisol synthesis in epidermis is induced by IL-1 and tissue injury.J Biol Chem. 2011; 286: 10265-10275Crossref PubMed Scopus (148) Google Scholar), there is little appreciation for the pathophysiological necessity of localized GC production in skin, especially because the systemic HPA axis can supply GC in abundance to most tissues. Patients with psoriasis are rarely treated with systemic GC and their HPA axis remains largely intact (Buske-Kirschbaum et al., 2006Buske-Kirschbaum A. Ebrecht M. Kern S. Hellhammer D.H. Endocrine stress responses in TH1-mediated chronic inflammatory skin disease (psoriasis vulgaris)—do they parallel stress-induced endocrine changes in TH2-mediated inflammatory dermatoses (atopic dermatitis)?.Psychoneuroendocrinology. 2006; 31: 439-446Crossref PubMed Scopus (66) Google Scholar, Harbuz et al., 2003Harbuz M. Chover-Gonzalez A. Jessop D. Hypothalamo-pituitary-adrenal axis and chronic immune activation.Ann N Y Acad Sci. 2003; 992: 99-106Crossref PubMed Scopus (78) Google Scholar), although a subpopulation of patients with psoriasis showed mild HPA axis perturbations during acute social stress (Richards et al., 2005Richards H.L. Ray D.W. Kirby B. Mason D. Plant D. Main C.J. et al.Response of the hypothalamic-pituitary-adrenal axis to psychological stress in patients with psoriasis.Br J Dermatol. 2005; 153: 1114-1120Crossref PubMed Scopus (91) Google Scholar) and psychological stress has been associated with skin barrier breakdown and cutaneous infections (Aberg et al., 2007Aberg K.M. Radek K.A. Choi E.-H.H. Kim D.-K.K. Demerjian M. Hupe M. et al.Psychological stress downregulates epidermal antimicrobial peptide expression and increases severity of cutaneous infections in mice.J Clin Invest. 2007; 117: 3339-3349Crossref PubMed Scopus (169) Google Scholar, Slominski, 2007Slominski A. A nervous breakdown in the skin: stress and the epidermal barrier.J Clin Invest. 2007; 117: 3166-3169Crossref PubMed Scopus (74) Google Scholar). The common use of topical GC-based therapies indicates that there is a local depletion of GC in psoriasis skin. Here we show that localized GC production is virtually ablated in psoriasis skin. Reduced bioavailability of cortisol was observed in uninvolved and lesional psoriasis skin, because of decreased synthesis and increased steroid sulfation, demonstrating that effective stress response is lost even in uninvolved skin. In the absence of a stressor, loss of skin GC production did not independently induce an inflammatory response, but localized GC production in mouse skin was found to prevent PMA-induced inflammation independently of the adrenal gland. Thus, defective de novo GC synthesis, from steroid enzymes to receptor, to our knowledge, provides a previously unreported pathogenic mechanism of psoriasis. StAR controls acute steroid synthesis and is downregulated in psoriasis, aging skin, and other inflammatory skin disorders (Hannen et al., 2011Hannen R.F. Michael A.E. Jaulim A. Bhogal R. Burrin M. Philott M.P. Steroid synthesis by primary human keratinocytes; implications for skin disease.Biochem Biophys Res Commun. 2011; 404: 62-67Crossref PubMed Scopus (64) Google Scholar, Manna et al., 2015Manna P.R. Stetson C.L. Daugherty C. Shimizu I. Syapin P.J. Garrel G. et al.Up-regulation of steroid biosynthesis by retinoid signaling: implications for aging.Mech Ageing Dev. 2015; 150: 74-82Crossref PubMed Scopus (26) Google Scholar, Slominski et al., 2015Slominski A.T. Manna P.R. Tuckey R.C. On the role of skin in the regulation of local and systemic steroidogenic activities.Steroids. 2015; 103: 72-88Crossref PubMed Scopus (124) Google Scholar, Tiala et al., 2007Tiala I. Suomela S. Huuhtanen J. Wakkinen J. Hölttä-Vuori M. Kainu K. et al.The CCHCR1 (HCR) gene is relevant for skin steroidogenesis and downregulated in cultured psoriatic keratinocytes.J Mol Med (Berl). 2007; 85: 589-601Crossref PubMed Scopus (40) Google Scholar). Although StAR is the rate-determining protein for steroidogenesis, simple observations of alterations in StAR expression do not provide information on the type of steroid being produced or non-StAR-mediated steroidogenesis. Steroid production is also regulated by MLN64, which is expressed abundantly in differentiating keratinocytes (Bose et al., 2000Bose H.S. Whittal R.M. Huang M.C. Baldwin M.A. Miller W.L. N-218 MLN64, a protein with StAR-like steroidogenic activity, is folded and cleaved similarly to StAR.Biochemistry. 2000; 39: 11722-11731Crossref PubMed Scopus (81) Google Scholar, Hannen et al., 2011Hannen R.F. Michael A.E. Jaulim A. Bhogal R. Burrin M. Philott M.P. Steroid synthesis by primary human keratinocytes; implications for skin disease.Biochem Biophys Res Commun. 2011; 404: 62-67Crossref PubMed Scopus (64) Google Scholar, Watari et al., 1997Watari H. Arakane F. Moog-Lutz C. Kallen C.B. Tomasetto C. Gerton G.L. et al.MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis.Proc Natl Acad Sci USA. 1997; 94: 8462-8467Crossref PubMed Scopus (205) Google Scholar). Thus, the absence of StAR does not necessarily equate to a complete loss of steroid production in skin; however, our study shows that GC production is clearly defective in psoriasis in addition to depleted StAR expression. GR expression was also ablated in lesional psoriatic keratinocytes. In contrast, another study detected GR in lesional psoriasis skin but found that it failed to translocate into the cell nucleus (Man et al., 2013Man X.Y. Li W. Chen J.Q. Zhou J. Landeck L. Zhang K.H. et al.Impaired nuclear translocation of glucocorticoid receptors: novel findings from psoriatic epidermal keratinocytes.Cell Mol Life Sci. 2013; 70: 2205-2220Crossref PubMed Scopus (30) Google Scholar). However, this study used a Han Chinese cohort; thus patients were of a different ethnicity to the UK-based study presented here. There are four GR single nucleotide polymorphism haplotypes that can regulate GC sensitivity that are also associated with psoriasis (Stevens et al., 2003Stevens A. Ray D.W. Zeggini E. John S. Richards H.L. Griffiths C.E. et al.Glucocorticoid sensitivity is determined by a specific glucocorticoid receptor h" @default.
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• W2598859771 date "2017-08-01" @default.
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• W2598859771 title "Dysfunctional Skin-Derived Glucocorticoid Synthesis Is a Pathogenic Mechanism of Psoriasis" @default.
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