Endogenous Glucocorticoid Deficiency in Psoriasis Promotes Inflammation and Abnormal Differentiation.
Endogenous Glucocorticoid Deficiency in Psoriasis Promotes Inflammation and Abnormal Differentiation.
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DOI：
10.1016/j.jid.2017.02.972
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发表时间：
2017-07
期刊：
影响因子：
--
通讯作者：
Gudjonsson JE
中科院分区：
文献类型：
--
作者：
Sarkar MK;Kaplan N;Tsoi LC;Xing X;Liang Y;Swindell WR;Hoover P;Aravind M;Baida G;Clark M;Voorhees JJ;Nair RP;Elder JT;Budunova I;Getsios S;Gudjonsson JE
参与维持银屑病皮肤局部炎症状态的因素仍然知之甚少。在这里，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的显著抑制导致皮质醇的局部缺乏。利用三维人体表皮模型，我们证明了糖皮质激素的生物合成受到促炎细胞因子的抑制，糖皮质激素缺乏会促进角质形成细胞的炎症反应。最后，我们在体外和体内表明，局部糖皮质激素治疗导致糖皮质激素生物合成基因表达的快速恢复与表皮分化的正常化和炎症反应的抑制一致。综上所述，我们的数据表明，银屑病皮肤局部糖皮质激素缺乏干扰表皮分化，促进持续和局部炎症反应。这可能为局部类固醇的作用机制提供了新的线索，并证明了内源性类固醇在维持表皮中的炎症和分化稳态中的关键作用。
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 pro-inflammatory 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.
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影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
6.5
作者：
Boix, Julia;Sevilla, Lisa M.;Perez, Paloma
通讯作者：
Perez, Paloma
影响因子：
10.3
作者：
BERNARD, BA;ROBINSON, SM;DARMON, M
通讯作者：
DARMON, M
影响因子：
6.5
作者：
Li, Bingshan;Tsoi, Lam C.;Swindell, William R.;Gudjonsson, Johann E.;Tejasvi, Trilokraj;Johnston, Andrew;Ding, Jun;Stuart, Philip E.;Xing, Xianying;Kochkodan, James J.;Voorhees, John J.;Kang, Hyun M.;Nair, Rajan P.;Abecasis, Goncalo R.;Elder, James T.
通讯作者：
Elder, James T.
影响因子：
29.7
作者：
Lowes MA;Suárez-Fariñas M;Krueger JG
通讯作者：
Krueger JG