Epidermal Mineralocorticoid Receptor Plays Beneficial and Adverse Effects in Skin and Mediates Glucocorticoid Responses
Epidermal Mineralocorticoid Receptor Plays Beneficial and Adverse Effects in Skin and Mediates Glucocorticoid Responses
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DOI：
10.1016/j.jid.2016.07.018
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发表时间：
2016-12-01
影响因子：
6.5
通讯作者：
Perez, Paloma
中科院分区：
文献类型：
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作者：
Boix, Julia;Sevilla, Lisa M.;Perez, Paloma
糖皮质激素（GC）调节皮肤稳态并对抗皮肤炎性疾病;然而，长期GC治疗的副作用限制了其治疗用途。GC结合并激活GC受体和盐皮质激素受体（MR），这些转录因子识别相同的激素反应元件。表皮MR是否介导有益或有害的GC效应对于改进基于GC的皮肤疗法具有极大的兴趣。MR表皮基因敲除小鼠表现出角质形成细胞增殖和分化增加，并表现出对GC诱导的表皮变薄的抗性。然而，至关重要的是，表皮MR的丧失使小鼠对炎症刺激和皮肤损伤更敏感。MR表皮基因敲除小鼠表现出对佛波醇12-肉豆蔻酸酯13-乙酸酯诱导的炎症的易感性增加，具有更高的细胞因子诱导。同样，培养的MR表皮敲除角质形成细胞具有增加的佛波醇12-肉豆蔻酸酯13-乙酸酯诱导的NF-kB活化，突出了MR的抗炎功能。在MR表皮敲除角质形成细胞中GC诱导的转录减少，至少部分是由于GC受体对含有激素响应元件的序列的募集减少。我们的研究结果支持表皮MR在成人皮肤稳态中的作用，并证明MR和GC受体在介导GC作用中的非冗余作用。
Glucocorticoids (GCs) regulate skin homeostasis and combat cutaneous inflammatory diseases; however, adverse effects of chronic GC treatments limit their therapeutic use. GCs bind and activate the GC receptor and the mineralocorticoid receptor (MR), transcription factors that recognize identical hormone responsive elements. Whether epidermal MR mediates beneficial or deleterious GC effects is of great interest for improving GC-based skin therapies. MR epidermal knockout mice exhibited increased keratinocyte proliferation and differentiation and showed resistance to GC-induced epidermal thinning. However, crucially, loss of epidermal MR rendered mice more sensitive to inflammatory stimuli and skin damage. MR epidermal knockout mice showed increased susceptibility to phorbol 12-myristate 13-acetate-induced inflammation with higher cytokine induction. Likewise, cultured MR epidermal knockout keratinocytes had increased phorbol 12-myristate 13-acetate-induced NF-kB activation, highlighting an anti-inflammatory function for MR. GC-induced transcription was reduced in MR epidermal knockout keratinocytes, at least partially due to decreased recruitment of GC receptor to hormone responsive element-containing sequences. Our results support a role for epidermal MR in adult skin homeostasis and demonstrate nonredundant roles for MR and GC receptor in mediating GC actions.