权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Functional specialization of proinflammatory dendritic cells in psoriasis

银屑病促炎树突状细胞的功能特化

基本信息

批准号：
289757521
负责人：
Professor Dr. Knut Schäkel
金额：
--
依托单位：
Universitäts-Hautklinik
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/289757521?language=en
关键词：
Functional specialization proinflammatory dendritic cells

项目摘要

Psoriasis is a common chronic inflammatory skin disease in which dendritic cells (DC) are thought to orchestrate the pathogenic Th17/Th1-dominated immune response. Our studies demonstrate the functional specialization of slan (6-sulfo LacNAc+) DC as an important proinflammatory DC subtype in psoriasis. Previously, we identified slanDC and reported on their proinflammatory function. In the meanwhile slanDC have also been described in other chronic inflammatory diseases such as lupus erythematosus, Crohns disease and multiple sclerosis. Skin lesion from psoriasis patients contain increased numbers of activated slanDC expressing the key proinflammatory molecules TNF-a, IL-23 and iNOS. Complexes of autologous nucleic acids and the antimicrobial peptide LL37 (Cathelicidin) triggering Toll-like receptors (TLR) are regarded as important stimuli for cell activation in psoriasis. For slanDC we could demonstrate expression of TLR7/8 and a high sensitivity to stimulation with LL37-complexed autologous RNA as well as synthetic TLR7- as well as TLR8- ligands. Stimulated slanDC can produce higher levels of the proinflammatory cytokines IL-23, IL-12, IL-1b as well as TNF-a than other DC subsets or monocytes and induce strong Th17/Th1-dominated immune responses. Our goal is to answer questions regarding the role of DC in the immunopathogenesis of psoriasis. Questions: 1. What is the in vivo relevance of slanDC for inducing and maintaining psoriasis skin inflammation? 2. Which unknown molecular and functional mechanisms allow slanDC to regulate the inflammatory immune response in psoriasis? 3. What is the spatial and temporal microanatomic localization of slanDC during the development and maintenance of psoriasis plaques? For these studies we will employ mouse models with human skin and leukocyte transplants, will develop targeting strategies for the depletion of slanDC, analyze gene expression of slanDC from lesional skin and correlate these findings with the microanatomic distribution of slanDC in the skin. We are convinced that the proposed study program has the potential to significantly increase our understanding of the immunopathogenesis of psoriasis and to identify new targets for therapeutic intervention in psoriasis. As slanDC play a proinflammatory role in different Th17/Th1 dominated chronic inflammatory diseases, the results of the propose work is potentially of broad interest.

银屑病是一种常见的慢性炎症性皮肤病，其中树突状细胞（DC）被认为是协调致病性Th 17/Th 1主导的免疫应答。我们的研究表明slan（6-sulfoLacNAc+）DC作为银屑病中重要的促炎DC亚型的功能特化。以前，我们确定了slanDC并报道了它们的促炎功能。与此同时，slanDC也在其他慢性炎症性疾病如红斑狼疮、克罗恩病和多发性硬化中被描述。银屑病患者的皮肤病变含有增加数量的表达关键促炎分子TNF-α、IL-23和iNOS的活化的slanDC。自体核酸和抗菌肽LL 37（Cathelicidin）触发Toll样受体（TLR）的复合物被认为是银屑病细胞活化的重要刺激物。对于slanDC，我们可以证明TLR 7/8的表达和对LL 37复合的自体RNA以及合成的TLR 7-和TLR 8-配体的刺激的高敏感性。经刺激的slanDC可产生比其他DC亚群或单核细胞更高水平的促炎细胞因子IL-23、IL-12、IL-1b以及TNF-α，并诱导强烈的Th 17/Th 1主导的免疫应答。我们的目标是回答关于DC在银屑病免疫发病机制中的作用的问题。问题：1. slanDC在诱导和维持银屑病皮肤炎症方面的体内相关性是什么？2.哪些未知的分子和功能机制允许slanDC调节银屑病的炎症免疫反应？3.在银屑病斑块的发展和维持过程中，slanDC的空间和时间显微解剖学定位是什么？对于这些研究，我们将采用小鼠模型与人类皮肤和白细胞移植，将开发靶向战略的损耗slanDC，分析基因表达的slanDC从病变皮肤和相关的这些发现与slanDC在皮肤中的微解剖分布。我们相信，拟议的研究计划有可能显着增加我们对银屑病免疫发病机制的理解，并确定新的治疗干预银屑病的目标。由于slanDC在不同的Th 17/Th 1占主导地位的慢性炎症性疾病中发挥促炎作用，因此所提出的工作的结果可能具有广泛的意义。