Attenuated Activation of Homeostatic Glucocorticoid in Keratinocytes Induces Alloknesis via Aberrant Artemin Production
Attenuated Activation of Homeostatic Glucocorticoid in Keratinocytes Induces Alloknesis via Aberrant Artemin Production
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DOI：
10.1016/j.jid.2018.02.010
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发表时间：
2018-07-01
影响因子：
6.5
通讯作者：
Katayama, Ichiro
中科院分区：
文献类型：
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作者：
Matsumoto, Akira;Murota, Hiroyuki;Katayama, Ichiro
剧烈的慢性瘙痒显著降低了特应性皮炎患者的生活质量，损害了日常活动。虽然不正常的瘙痒感觉可以由无害的刺激引起，也就是所谓的同种异体膝痛，但驱动这一过程的机制仍然不清楚。众所周知，心理和环境刺激会加重特应性皮炎症状。近年来，角质形成细胞中表达的酶11β-羟基类固醇脱氢酶-1(HSD11β1)被认为通过激活内源性糖皮质激素来维持对环境刺激的动态平衡。为了研究HSD11β1在角质形成细胞中的作用，我们建立了角质形成细胞特异性Hsd11b1基因敲除小鼠(Hsd11b1(KC-/-))，并分析了皮肤表型。Hsd11b1(KC-/-)小鼠表现出异常的皮肤神经支配和皮肤敏感性，包括光机械刺激诱发的瘙痒(即同种异体膝曲)。Hsd11b1(KC-/-)小鼠角质形成细胞异常产生的青蒿素诱导的内源性糖皮质激素激活减弱参与了同种异体膝的形成。最后，我们观察到阿尔茨海默病患者和非阿尔茨海默病患者皮肤中HSD11β1和青蒿素的表达呈显著负相关。这些结果表明，维持皮肤表皮动态平衡的内源性糖皮质激素既影响皮肤神经支配，也影响皮肤感觉。HSD11β1活性的调节可能成为敏感或瘙痒皮肤的治疗靶点。
Intense chronic itch significantly reduces quality of life for atopic dermatitis patients, impairing daily activity. Although abnormal itch sensation can be induced by innocuous stimuli, known as alloknesis, the mechanisms driving this process remain obscure. Psychological and environmental stimuli are known to aggravate atopic dermatitis symptoms. Recently, the enzyme 11 beta-hydroxysteroid dehydrogenase-1 (HSD11 beta 1), which is expressed in keratinocytes, has been implicated in maintaining homeostasis against environmental stimuli by activating endogenous glucocorticoids. To investigate the role of HSD11 beta 1 in keratinocytes, we generated keratinocyte-specific Hsd11b1-knockout (Hsd11b1(KC-/-)) mice and analyzed skin phenotype. Hsd11b1(KC-/-)mice exhibited abnormal cutaneous innervation and skin sensitivity, including light mechanical stimulus-evoked itch (i.e., alloknesis). Attenuated endogenous glucocorticoid activation induced by aberrant artemin production in keratinocytes was involved in alloknesis in Hsd11b1(KC-/-) mice. Finally, we observed a significant negative correlation between expression of HSD11 beta 1 and artemin in human skin with and without AD. These results suggest that endogenous glucocorticoids that maintain skin homeostasis in the epidermis affect both skin innervation and cutaneous sensation. Modulation of HSD11 beta 1 activation could be a therapeutic target for sensitive or itchy skin.