title: 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.
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Institute of Cell and Molecular Science, Bart's and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. Electronic address: r.f.hannen@qmul.ac.uk.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Hannen
authors.affiliation: Centre for Synaptic Plasticity, University of Bristol, Dorothy Hodgkin Building, Bristol, UK; Neuroepidemiology and Ageing Research Unit, Imperial Collage, London, UK.
authors.forename: Chinedu
authors.initials: C
authors.lastname: Udeh-Momoh
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Institute of Cell and Molecular Science, Bart's and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: James
authors.initials: J
authors.lastname: Upton
authors.affiliation: Department of Biochemistry, Addenbrookes Hospital, Cambridge, UK; LGC, Sport and Specialised Analytical Services, Fordham, Cambridgeshire, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Wright
authors.affiliation: The School of Biological and Chemical Sciences, Queen Mary University of London, London, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Michael
authors.affiliation: Department of Dermatology, The Royal London Hospital, Whitechapel, London, UK.
authors.forename: Abha
authors.initials: A
authors.lastname: Gulati
authors.affiliation: Department of Dermatology, Whipps Cross Hospital, Leytonstone, London, UK.
authors.forename: Shefali
authors.initials: S
authors.lastname: Rajpopat
authors.affiliation: Department of Dermatology, The Royal London Hospital, Whitechapel, London, UK.
authors.forename: Nicky
authors.initials: N
authors.lastname: Clayton
authors.affiliation: Department of Biochemistry, Addenbrookes Hospital, Cambridge, UK.
authors.forename: David
authors.initials: D
authors.lastname: Halsall
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Jacky
authors.initials: J
authors.lastname: Burrin
authors.affiliation: Centre for Pharmacology and Biochemistry, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Roderick
authors.initials: R
authors.lastname: Flower
authors.affiliation: Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas, Valencia, Spain.
authors.forename: Lisa
authors.initials: L
authors.lastname: Sevilla
authors.affiliation: Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas, Valencia, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Latorre
authors.affiliation: Anglia-Ruskin University, Chelmsford, Essex, UK.
authors.forename: James
authors.initials: J
authors.lastname: Frame
authors.affiliation: Centre for Synaptic Plasticity, University of Bristol, Dorothy Hodgkin Building, Bristol, UK.
authors.forename: Stafford
authors.initials: S
authors.lastname: Lightman
authors.affiliation: Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas, Valencia, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Perez
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Institute of Cell and Molecular Science, Bart's and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Philpott
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D015151:Immunoblotting; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011565:Psoriasis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012313:RNA / Q000235:genetics*; D011863:Radioimmunoassay; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D011965:Receptors, Glucocorticoid; D012313:RNA