title: Endogenous Glucocorticoid Deficiency in Psoriasis Promotes Inflammation and Abnormal Differentiation.
abstract: The factors involved in maintaining a localized inflammatory state in psoriatic skin remain poorly understood. Here, we demonstrate through metabolomic and transcriptomic profiling marked suppression of glucocorticoid biosynthesis in the epidermis of psoriatic skin leading to localized deficiency of cortisol. Utilizing a 3D human epidermis model, we demonstrate that glucocorticoid biosynthesis is suppressed by proinflammatory cytokines and that glucocorticoid deficiency promotes inflammatory responses in keratinocytes. Finally, we show in vitro and in vivo that treatment with topical glucocorticoids leads to rapid restoration of glucocorticoid biosynthesis gene expression coincident with normalization of epidermal differentiation and suppression of inflammatory responses. Taken together, our data suggest that localized glucocorticoid deficiency in psoriatic skin interferes with epidermal differentiation and promotes a sustained and localized inflammatory response. This may shed new light on the mechanism of action of topical steroids, and demonstrates the critical role of endogenous steroid in maintaining both inflammatory and differentiation homeostasis in the epidermis.
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Mrinal K
authors.initials: MK
authors.lastname: Sarkar
authors.affiliation: Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Nihal
authors.initials: N
authors.lastname: Kaplan
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA; Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Lam C
authors.initials: LC
authors.lastname: Tsoi
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Xianying
authors.initials: X
authors.lastname: Xing
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Swindell
authors.affiliation: Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Hoover
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Aravind
authors.affiliation: Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Gleb
authors.initials: G
authors.lastname: Baida
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Clark
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Voorhees
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Rajan P
authors.initials: RP
authors.lastname: Nair
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
authors.affiliation: Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Budunova
authors.affiliation: Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Spiro
authors.initials: S
authors.lastname: Getsios
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA. Electronic address: johanng@med.umich.edu.
authors.forename: Johann E
authors.initials: JE
authors.lastname: Gudjonsson
mesh_terms: D002454:Cell Differentiation; D004797:Enzyme-Linked Immunosorbent Assay; D004817:Epidermis / Q000378:metabolism; D005938:Glucocorticoids / Q000096:biosynthesis*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D013058:Mass Spectrometry; D011565:Psoriasis / Q000378:metabolism* / Q000473:pathology
chemical_list: D005938:Glucocorticoids