Functional specialization of proinflammatory dendritic cells in psoriasis

银屑病是一种常见的慢性炎症性皮肤病，树突状细胞(DC)被认为协调致病的Th17/Th1主导的免疫反应。我们的研究表明，SLAN(6-Sulo LacNAc+)DC是银屑病中一个重要的促炎DC亚型。在此之前，我们鉴定了slanDC，并报道了它们的促炎功能。与此同时，slanDC也被描述为其他慢性炎症性疾病，如红斑狼疮、克罗恩氏病和多发性硬化症。银屑病患者的皮损含有大量活化的slanDC，表达关键的促炎分子TNF-a、IL-23和iNOS。自体核酸与激活Toll样受体(TLR)的抗菌肽LL37的复合体被认为是银屑病细胞活化的重要刺激因素。对于slanDC，我们可以证明TLR7/8的表达以及对LL37-复合自体RNA以及合成的TLR7-和TLR8-配体的刺激高度敏感。与其他DC亚群或单核细胞相比，受刺激的slanDC可产生更高水平的促炎细胞因子IL-23、IL-12、IL-1b和肿瘤坏死因子-α，并诱导以Th17/Th1为主的免疫应答。我们的目标是回答有关DC在银屑病免疫发病机制中的作用的问题。问：1.slanDC在体内与银屑病皮肤炎症的诱导和维持有什么相关性？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.slanDC在银屑病斑块形成和维持过程中的空间和时间微解剖定位是什么？在这些研究中，我们将使用人类皮肤和白细胞移植的小鼠模型，将开发耗尽slanDC的靶向策略，分析皮损皮肤slanDC的基因表达，并将这些发现与slanDC在皮肤中的显微解剖分布相关联。我们相信，拟议的研究计划有可能显著增加我们对牛皮癣免疫发病机制的了解，并为牛皮癣的治疗干预确定新的靶点。由于slanDC在不同的Th17/Th1主导的慢性炎症性疾病中发挥促炎作用，拟议工作的结果可能会引起广泛的兴趣。

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.