Role of the Transcription Factor NFATc1 in Psoriasis and Psoriasis-like Skin Inflammation

银屑病是一种常见的炎症性皮肤病，影响2-3%的人口，严重影响生活质量。这种疾病通常与(牛皮癣)关节炎、心血管、代谢和其他并存疾病有关。鳞屑、浸润性红斑是银屑病的临床特征，它反映角质形成细胞过度增殖和异常分化，以及真皮和表皮的白细胞浸润。今天，银屑病被认为是一种T细胞控制的全身性炎症性疾病，受遗传易感性和环境因素的调节。到目前为止，一种在很大程度上被病理忽视的细胞类型是B淋巴细胞。利用一种被广泛认可的银屑病样皮肤炎症的小鼠模型，该模型依赖于重复使用Toll样受体(TLR)-7激动剂咪喹莫特(Imq)，我们最近发现，B淋巴细胞的缺乏导致皮肤炎症的大规模加重。相比之下，B淋巴细胞选择性切除转录因子NFATc1的小鼠几乎没有发生任何银屑病样炎症(Alrefai等人，自然通讯7：11724，DOI：10.1038/nComms11724(2016年))。这些观察结果可能归因于NFATc1介导的B淋巴细胞中抗炎细胞因子白介素10(IL-10)的转录下调，而B淋巴细胞控制Th1和Th17驱动的炎症。这项跨学科项目建议的目的是(I)确定B淋巴细胞的发育阶段和(亚)群体(S)，在其中NFATc1调节(S)小鼠皮肤炎症的发展；(Ii)阐明B细胞(包括产生IL-10的调节性B细胞(Bregs))是否以及如何影响人类银屑病的发生和维持。此外，我们(Iii)计划阐明NFATc1对B淋巴细胞新陈代谢的影响，并在皮肤炎症的背景下研究其功能后果。该工作计划将包括对转基因小鼠的细胞、分子和免疫学研究，以确定相关的B淋巴细胞亚群，并系统地表征NFATc1调节的基因表达程序。这些发现随后将在皮损和非皮损的牛皮癣皮肤以及牛皮癣患者和健康对照组的循环淋巴细胞中得到验证。为了最终证明Bregs在人类银屑病中的预期作用，我们将进行人银屑病皮肤到SCID小鼠的异种移植，然后进行人类淋巴细胞的自体适应性移植。最后，我们将研究NFATc1对淋巴细胞代谢的影响，以前瞻性地为银屑病等慢性皮肤炎的新治疗策略铺平道路。

Psoriasis is a common inflammatory skin disease affecting 2-3 % of the population that considerably impairs the quality of life. The disease is often associated with (psoriatic) arthritis, cardiovascular, metabolic and other co-morbidities. Scaling, infiltration and erythema are the clinical hallmarks of psoriasis, which reflect excessive proliferation and aberrant differentiation of keratinocytes as well as leukocyte infiltration of dermis and epidermis. Today, psoriasis is considered as a T cell-controlled systemic inflammatory disease that is modulated by genetic susceptibility and environmental factors. A cell type that -so far- has pathogenetically largely been neglected are B lymphocytes. Using a widely recognized mouse model of psoriasis-like skin inflammation that relies on the repetitive epicutaneous application of the Toll-Like Receptor (TLR)-7 agonist imiquimod (IMQ) we very recently showed that the absence of B lymphocytes resulted in a massive aggravation of skin inflammation. In contrast, mice with B lymphocyte-selective ablation of the transcription factor NFATc1 developed hardly any psoriasiform inflammation (Alrefai et al., Nature Communications 7:11724, doi: 10.1038/ncomms11724 (2016)). These observations could be attributed to the NFATc1-mediated transcriptional down-regulation of the anti-inflammatory cytokine interleukin-10 (IL-10) in B lymphocytes, which controlled Th1- and Th17-driven inflammation. The aim of this interdisciplinary project proposal is (i) to identify the developmental stages and (sub-) population(s) of B lymphocytes in which NFATc1 regulate(s) the development of murine skin inflammation and (ii) to elucidate whether and how B cells (including IL-10-producing regulatory B cells (Bregs)) affect the development and maintenance of psoriasis in humans. Moreover, we (iii) plan to elucidate the influence of NFATc1 on the metabolism of B lymphocytes and study its functional consequences in the context of skin inflammation. The work program will include cellular, molecular and immunological studies of genetically modified mice to identify relevant subpopulations of B lymphocytes and to systematically characterize NFATc1-regulated gene expression programs. Findings will be subsequently validated in lesional and non-lesional human psoriatic skin as well as in circulating lymphocytes of psoriasis patients and healthy controls. To finally proof the anticipated role of Bregs in human psoriasis, we will perform xenotransplantation of human psoriatic skin to SCID mice followed by the autologous adaptive transfer of human lymphocytes. Finally, we will study the effect of NFATc1 on the metabolism of lymphocytes to perspectively pave the way for novel therapeutic strategies for chronic skin inflammation such as psoriasis.