Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
The NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, CA, USA.
EMBO Rep. 2023 Jul 5;24(7):e56214. doi: 10.15252/embr.202256214. Epub 2023 May 30.
Skin epidermis constitutes the outer permeability barrier that protects the body from dehydration, heat loss, and myriad external assaults. Mechanisms that maintain barrier integrity in constantly challenged adult skin and how epidermal dysregulation shapes the local immune microenvironment and whole-body metabolism remain poorly understood. Here, we demonstrate that inducible and simultaneous ablation of transcription factor-encoding Ovol1 and Ovol2 in adult epidermis results in barrier dysregulation through impacting epithelial-mesenchymal plasticity and inflammatory gene expression. We find that aberrant skin immune activation then ensues, featuring Langerhans cell mobilization and T cell responses, and leading to elevated levels of secreted inflammatory factors in circulation. Finally, we identify failure to gain body weight and accumulate body fat as long-term consequences of epidermal-specific Ovol1/2 loss and show that these global metabolic changes along with the skin barrier/immune defects are partially rescued by immunosuppressant dexamethasone. Collectively, our study reveals key regulators of adult barrier maintenance and suggests a causal connection between epidermal dysregulation and whole-body metabolism that is in part mediated through aberrant immune activation.
皮肤表皮构成了保护身体免受脱水、热量散失和各种外部侵袭的外部渗透性屏障。在不断受到挑战的成年皮肤中维持屏障完整性的机制，以及表皮失调如何塑造局部免疫微环境和全身代谢，这些仍然知之甚少。在这里，我们证明了在成年表皮中诱导性和同时敲除转录因子编码基因 Ovol1 和 Ovol2 会通过影响上皮-间充质可塑性和炎症基因表达导致屏障失调。我们发现随后会出现异常的皮肤免疫激活，表现为朗格汉斯细胞动员和 T 细胞反应，并导致循环中分泌的炎症因子水平升高。最后，我们确定表皮特异性 Ovol1/2 缺失的长期后果是体重增加和体脂积累失败，并且表明这种全身代谢变化以及皮肤屏障/免疫缺陷部分可以通过免疫抑制剂地塞米松来挽救。总的来说，我们的研究揭示了成年屏障维持的关键调节剂，并表明表皮失调与全身代谢之间存在因果关系，部分是通过异常免疫激活介导的。
