The surface of the skin is continually exposed to pro-inflammatory stimuli; however, it is unclear why it is not constantly inflamed due to this exposure. Here, we showed undifferentiated keratinocytes residing in the deep epidermis could trigger a strong inflammatory response due to their high expression of pattern recognition receptors (PRRs) that detect damage or pathogens. As keratinocytes differentiated, they migrated outward toward the surface of the skin and decreased their PRR expression, which led to dampened immune responses. ZNF750, a transcription factor expressed only in differentiated keratinocytes, recruited the histone demethylase KDM1A/LSD1 to silence genes coding for PRRs (TLR3, IFIH1/MDA5, and DDX58/RIG1). Loss of ZNF750 or KDM1A in human keratinocytes or mice resulted in sustained and excessive inflammation resembling psoriatic skin, which could be restored to homeostatic conditions upon silencing of TLR3. Our findings explain how the skin’s surface prevents excessive inflammation through ZNF750- and KDM1A-mediated suppression of PRRs.

中文翻译：

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转录调节因子 ZNF750 和 LSD1/KDM1A 通过沉默模式识别受体来抑制皮肤表面的炎症


皮肤表面不断暴露在促炎刺激下;然而，目前尚不清楚为什么它不会因为这种暴露而持续发炎。在这里，我们发现驻留在表皮深层的未分化角质形成细胞可以触发强烈的炎症反应，因为它们高表达检测损伤或病原体的模式识别受体 （PRR）。随着角质形成细胞的分化，它们向外迁移到皮肤表面并降低其 PRR 表达，从而导致免疫反应减弱。ZNF750 是一种仅在分化的角质形成细胞中表达的转录因子，它募集组蛋白去甲基化酶 KDM1A/LSD1 以沉默编码 PRR 的基因 （TLR3、IFIH1/MDA5 和 DDX58/RIG1）。人角质形成细胞或小鼠中 ZNF750 或 KDM1A 的缺失导致类似于银屑病皮肤的持续和过度炎症，在 TLR3 沉默后可以恢复到稳态状态。我们的研究结果解释了皮肤表面如何通过 ZNF750 和 KDM1A 介导的抑制 PRR 来防止过度炎症。