NFAT Transcription Factors Control the Fate of Keratinocytes and Lymphocytes in Skin Homeostasis and Inflammatory Skin Diseases

皮肤稳态依赖于严格调节的先天和适应性免疫反应。分子免疫水平的免疫失衡可促进炎症性皮肤病，炎症性皮肤病通常与淋巴细胞皮肤浸润和角化细胞分化的连续改变有关。NFAT家族的转录因子在这些过程中发挥重要作用，特别是通过控制T淋巴细胞的活性。在体外角质形成细胞/T细胞共培养模型中使用缺乏NFATc1和nfatc2的T细胞，我们最近发现这些T细胞几乎完全阻止了吸引淋巴细胞的趋化因子CXCL9和CXCL10的角质形成细胞合成。此外，我们正在进行的工作暗示了NFAT家族成员NFAT5在角化细胞分化和表皮完整性中的意想不到的作用。主要的nfat5控制基因包括klikrein 7 （KLK7）和matrix metalloproteinase 3 (MMP3)，它们促进角质形成细胞向角质细胞的分化。利用典型炎性皮肤病（地衣样皮炎、特应性湿疹）的小鼠模型，我们将通过条件NFATc1和NFAT5敲除小鼠，研究NFAT因子在炎症过程和病理性角化细胞分化中的作用。一方面，我们想了解NFAT因子在引流淋巴结（自身）抗原特异性淋巴细胞的第一步激活和T淋巴细胞侵入皮肤中的重要性。另一方面，我们打算研究它们在稳态和炎症条件下对角质细胞分化的直接和间接影响。工作计划包括使用分子，细胞生物学和免疫学方法鉴定转基因小鼠中相关的T淋巴细胞亚群，并在淋巴细胞和表皮中全基因组表征nfat调节的基因表达程序。研究结果将通过分析皮损性和非皮损性人类皮肤以及来自扁平苔藓和特应性湿疹患者和对照个体的循环淋巴细胞进行评估。我们提出的项目将更多地阐明控制人类炎症性皮肤病的分子机制，以专门解决nfat依赖性信号通路的新治疗方法。

Skin homeostasis relies on tightly regulated innate and adaptive immune responses. Immunologic dysbalances at the molecular immunological level can promote inflammatory skin diseases, which are often associated with lymphocytic skin infiltration and consecutive alteration of keratinocyte differentiation.The transcription factors of the NFAT family play an important role in these processes, especially by controlling the activity of T lymphocytes. Using NFATc1- and NFATc2-deficient T-cells in an in vitro keratinocyte/T-cell co-culture model we could recently show that these T cells almost completely stop the keratinocytic synthesis of the lymphocyte-attracting chemokines CXCL9 and CXCL10. Furthermore, our ongoing work hints to an unexpected role of NFAT5, a member of the NFAT family, in the differentiation of keratinocytes and epidermal integrity. Among major putative NFAT5-controlled genes are kallikrein 7 (KLK7) and matrix metalloproteinase 3 (MMP3), which promote the differentiation of keratinocytes to corneocytes.Using mouse models of prototypical inflammatory skin diseases (lichenoid dermatitis, atopic eczema) we will investigate the role of NFAT factors in inflammatory processes and pathological keratinocyte differentiation by applying conditional NFATc1 and NFAT5 knockout mice. On the one hand, we want to understand the importance of NFAT factors for the first activation steps of (auto-)antigen-specific lymphocytes in the draining lymph nodes and for T lymphocyte invasion into the skin. On the other hand, we intend to investigate their direct and indirect influence on keratinocyte differentiation under steady-state and inflammatory conditions. The work program includes the use of molecular, cell biological and immunological methods to identify relevant T lymphocyte subpopulations in genetically modified mice and to genome-wide characterize NFAT-regulated gene expression programs in lymphocytes and the epidermis. Findings will be evaluated in parallel by analysis of lesional and non-lasional human skin and circulating lymphocytes from patients with lichen planus and atopic eczema as well as control individuals.Our proposed project will shed more light on the molecular mechanisms controlling human inflammatory skin diseases to specifically tackle NFAT-dependent signaling pathways for novel therapeutic approaches.