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

皮肤的动态平衡依赖于严格调控的先天和适应性免疫反应。分子免疫水平的免疫失衡可以促进炎症性皮肤病的发生，而炎症性皮肤病往往与淋巴细胞性皮肤浸润和角质形成细胞分化的连续性改变有关，NFAT家族的转录因子在这些过程中发挥着重要作用，特别是通过控制T淋巴细胞的活性。利用NFATc1和NFATc2缺陷的T细胞在体外角质形成细胞/T细胞共培养模型中，我们最近发现这些T细胞几乎完全停止了吸引淋巴细胞的趋化因子CXCL9和CXCL10的角质形成细胞的合成。此外，我们正在进行的工作提示，NFAT家族成员NFAT5在角质形成细胞分化和表皮完整性方面发挥了意想不到的作用。在NFAT5控制的主要基因中有激肽释放酶7(KLK7)和基质金属蛋白酶3(MMP3)，它们促进角质形成细胞向角质形成细胞的分化。我们将利用典型炎症性皮肤病(苔藓样皮炎，特应性湿疹)的小鼠模型，通过条件NFATc1和NFAT5基因敲除小鼠来研究NFAT因子在炎症过程和病理角质形成细胞分化中的作用。一方面，我们想要了解NFAT因子在引流淋巴结中(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形成细胞分化的直接和间接影响。该工作计划包括使用分子、细胞生物学和免疫学方法识别转基因小鼠中相关的T淋巴细胞亚群，并在全基因组范围内表征淋巴细胞和表皮中NFAT调节的基因表达程序。研究结果将通过对扁平苔藓和特应性湿疹患者的皮损和非皮损皮肤和循环淋巴细胞以及对照组的分析进行平行评估。我们提出的项目将进一步阐明控制人类炎症性皮肤病的分子机制，为新的治疗方法专门处理NFAT依赖的信号通路。

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.