Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, United States of America.
PLoS One. 2012;7(12):e51262. doi: 10.1371/journal.pone.0051262. Epub 2012 Dec 20.
Ctip2 is crucial for epidermal homeostasis and protective barrier formation in developing mouse embryos. Selective ablation of Ctip2 in epidermis leads to increased transepidermal water loss (TEWL), impaired epidermal proliferation, terminal differentiation, as well as altered lipid composition during development. However, little is known about the role of Ctip2 in skin homeostasis in adult mice.
METHODOLOGY/PRINCIPAL FINDINGS: To study the role of Ctip2 in adult skin homeostasis, we utilized Ctip2(ep-/-) mouse model in which Ctip2 is selectively deleted in epidermal keratinocytes. Measurement of TEWL, followed by histological, immunohistochemical, and RT-qPCR analyses revealed an important role of Ctip2 in barrier maintenance and in regulating adult skin homeostasis. We demonstrated that keratinocytic ablation of Ctip2 leads to atopic dermatitis (AD)-like skin inflammation, characterized by alopecia, pruritus and scaling, as well as extensive infiltration of immune cells including T lymphocytes, mast cells, and eosinophils. We observed increased expression of T-helper 2 (Th2)-type cytokines and chemokines in the mutant skin, as well as systemic immune responses that share similarity with human AD patients. Furthermore, we discovered that thymic stromal lymphopoietin (TSLP) expression was significantly upregulated in the mutant epidermis as early as postnatal day 1 and ChIP assay revealed that TSLP is likely a direct transcriptional target of Ctip2 in epidermal keratinocytes.
CONCLUSIONS/SIGNIFICANCE: Our data demonstrated a cell-autonomous role of Ctip2 in barrier maintenance and epidermal homeostasis in adult mice skin. We discovered a crucial non-cell autonomous role of keratinocytic Ctip2 in suppressing skin inflammatory responses by regulating the expression of Th2-type cytokines. It is likely that the epidermal hyperproliferation in the Ctip2-lacking epidermis may be secondary to the compensatory response of the adult epidermis that is defective in barrier functions. Our results establish an initiating role of epidermal TSLP in AD pathogenesis via a novel repressive regulatory mechanism enforced by Ctip2.
Ctip2 对于胚胎发育期小鼠的表皮稳态和保护屏障的形成至关重要。在表皮中选择性地剔除 Ctip2 会导致经表皮水分丢失（TEWL）增加、表皮增殖受损、终末分化受损以及在发育过程中脂质组成改变。然而，目前对于 Ctip2 在成年小鼠皮肤稳态中的作用知之甚少。
方法/主要发现：为了研究 Ctip2 在成年皮肤稳态中的作用，我们利用 Ctip2（ep-/-）小鼠模型，该模型中 Ctip2 选择性地在表皮角质形成细胞中缺失。TEWL 测量，随后的组织学、免疫组织化学和 RT-qPCR 分析表明 Ctip2 在屏障维持和调节成年皮肤稳态中具有重要作用。我们证明，角质形成细胞中 Ctip2 的缺失会导致特应性皮炎（AD）样皮肤炎症，表现为脱发、瘙痒和鳞屑，以及包括 T 淋巴细胞、肥大细胞和嗜酸性粒细胞在内的大量免疫细胞浸润。我们观察到突变皮肤中 Th2 型细胞因子和趋化因子的表达增加，以及与人类 AD 患者相似的全身免疫反应。此外，我们发现胸腺基质淋巴细胞生成素（TSLP）的表达在突变表皮中早在出生后第 1 天就显著上调，ChIP 测定显示 TSLP 可能是表皮角质形成细胞中 Ctip2 的直接转录靶标。
结论/意义：我们的数据表明 Ctip2 在成年小鼠皮肤的屏障维持和表皮稳态中具有细胞自主作用。我们发现角质形成细胞 Ctip2 通过调节 Th2 型细胞因子的表达在抑制皮肤炎症反应中具有重要的非细胞自主作用。Ctip2 缺失的表皮中表皮的过度增殖可能是由于屏障功能缺陷的成年表皮的代偿反应。我们的结果通过 Ctip2 强制实施的新型抑制性调节机制确立了表皮 TSLP 在 AD 发病机制中的起始作用。
