Sarkar Mrinal K, Kaplan Nihal, Tsoi Lam C, Xing Xianying, Liang Yun, Swindell William R, Hoover Paul, Aravind Maya, Baida Gleb, Clark Matthew, Voorhees John J, Nair Rajan P, Elder James T, Budunova Irina, Getsios Spiro, Gudjonsson Johann E
Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
J Invest Dermatol. 2017 Jul;137(7):1474-1483. doi: 10.1016/j.jid.2017.02.972. Epub 2017 Mar 1.
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.
银屑病皮肤中维持局部炎症状态的相关因素仍知之甚少。在此，我们通过代谢组学和转录组学分析表明，银屑病皮肤表皮中糖皮质激素生物合成受到显著抑制，导致皮质醇局部缺乏。利用三维人表皮模型，我们证明促炎细胞因子可抑制糖皮质激素生物合成，且糖皮质激素缺乏会促进角质形成细胞中的炎症反应。最后，我们在体外和体内均表明，局部应用糖皮质激素治疗可使糖皮质激素生物合成基因表达迅速恢复，同时表皮分化正常化并抑制炎症反应。综上所述，我们的数据表明，银屑病皮肤中的局部糖皮质激素缺乏会干扰表皮分化并促进持续的局部炎症反应。这可能为局部类固醇的作用机制提供新的线索，并证明内源性类固醇在维持表皮炎症和分化稳态中的关键作用。
