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

转录因子 NFATc1 在银屑病和银屑病样皮肤炎症中的作用

• 批准号: 327393219
• 负责人: Professor Dr. Matthias Goebeler
• 金额: --
• 依托单位: Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/327393219?language=en
• 关键词: Role; Transcription; Factor; NFATc1; Psoriasis

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.

银屑病是一种常见的炎症性皮肤病，影响2- 3%的人口，大大损害生活质量。该疾病通常与（银屑病）关节炎、心血管、代谢和其他共病有关。鳞屑、浸润和红斑是银屑病的临床特征，其反映了角质形成细胞的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。迄今为止，在病理学上被忽视的一种细胞类型是B淋巴细胞。使用广泛认可的银屑病样皮肤炎症的小鼠模型，该模型依赖于Toll样受体（TLR）-7激动剂咪喹莫特（IMQ）的重复表皮应用，我们最近表明，B淋巴细胞的缺乏导致皮肤炎症的大量加重。相比之下，用B淋巴细胞选择性消融转录因子NFATc 1的小鼠几乎不发生任何银屑病样炎症（Alrefai等人，Nature Communications 7：11724，doi：10.1038/ncomms11724（2016））。这些观察结果可能归因于NFATc 1介导的B淋巴细胞中抗炎细胞因子白细胞介素-10（IL-10）的转录下调，其控制Th 1和Th 17驱动的炎症。本跨学科项目提案的目的是（i）确定NFATc 1调节小鼠皮肤炎症发展的B淋巴细胞的发育阶段和（亚）群体，（ii）阐明B细胞（包括产生IL-10的调节性B细胞（BCL 1））是否以及如何影响人类银屑病的发展和维持。此外，我们（iii）计划阐明NFATc 1对B淋巴细胞代谢的影响，并研究其在皮肤炎症背景下的功能后果。该工作计划将包括转基因小鼠的细胞、分子和免疫学研究，以鉴定相关的B淋巴细胞亚群，并系统地表征NFATc 1调节的基因表达程序。随后将在银屑病患者和健康对照的皮损和非皮损人类银屑病皮肤以及循环淋巴细胞中验证结果。为了最终证明Bceptin在人类银屑病中的预期作用，我们将对SCID小鼠进行人类银屑病皮肤的异种移植，然后进行人类淋巴细胞的自体适应性转移。最后，我们将研究NFATc 1对淋巴细胞代谢的影响，为慢性皮肤炎症如银屑病的新治疗策略铺平道路。