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，其中树突状细胞（DC）被认为协调致病性Th17/ th1主导的免疫反应。我们的研究表明，slan (6-sulfo LacNAc+) DC在银屑病中是一种重要的促炎DC亚型。之前，我们发现了slanDC并报道了它们的促炎功能。同时，slanDC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症中也有报道。牛皮癣患者的皮肤病变含有表达关键促炎分子TNF-a、IL-23和iNOS的活化slanDC数量增加。自体核酸复合物和抗菌肽LL37 （Cathelicidin）触发toll样受体（TLR）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TLR7/8的表达，并且对ll37络合的自体RNA以及合成的TLR7-和TLR8-配体的刺激具有高度敏感性。受刺激的slanDC可以产生比其他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和TNF-a，并诱导强烈的Th17/ th1主导的免疫反应。我们的目标是回答有关DC在牛皮癣免疫发病机制中的作用的问题。问题:1。slanDC在诱导和维持牛皮癣皮肤炎症中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在空间和时间上的显微解剖定位是什么？在这些研究中，我们将采用人类皮肤和白细胞移植的小鼠模型，将开发slanDC消耗的靶向策略，分析病变皮肤中slanDC的基因表达，并将这些发现与皮肤中slanDC的微观解剖分布联系起来。我们相信，拟议的研究计划有可能显著增加我们对银屑病免疫发病机制的理解，并确定银屑病治疗干预的新靶点。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，因此提出的工作结果可能具有广泛的兴趣。

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.