Regulation of TSLP-Mediated Skin Inflammation

项目总结/摘要 皮肤是一种屏障组织，具有与外部环境和自身接触的大表面积。 微生物植物群。因此，皮肤中的免疫反应必须严格调节，以避免不必要的， 对无害的环境物质和抗原的潜在有害反应，同时允许 对多种皮肤病原体的反应。免疫反应失调的后果 皮肤可以是可怕，包括炎性疾病，如牛皮癣、硬皮病和天疱疮 以及导致急性和慢性特应性皮炎（AD）和过敏性接触的过敏反应 皮炎（ACD）。我们已经证明，细胞因子胸腺基质的转基因过表达 淋巴细胞生成素（TSLP）特异性地在皮肤中的释放导致类似慢性AD的严重皮肤炎症。 这种炎症的特征是CD 4 + T细胞的过度活化和CD 4 + T细胞的强烈偏倚的发展。 Th 2应答，血清IgE水平升高，以及严重的真皮浸润T细胞、肥大细胞和嗜酸性粒细胞。 令人惊讶的是，缺乏T细胞的TSLP过表达小鼠仍然发展出特征性的皮肤炎症， 这表明骨髓细胞足以在皮肤中诱导TSLP诱导的炎症。的 本研究提出的实验的中心假设是， 角质形成细胞激活皮肤中的常驻骨髓细胞，导致皮肤Th 2细胞的诱导， 反应和皮肤过敏性炎症。皮肤中TSLP表达严重失调导致 骨髓细胞过度活化，导致严重的皮肤免疫病理学和强烈的Th 2- 介导的炎症。为了验证这些假设，并进一步确定TSLP在驱动过敏反应中的作用， 炎症，我们将1）定义导致皮肤中TSLP表达的分子途径，2）确定 常驻皮肤骨髓细胞在引发TSLP介导的皮肤炎症中的作用，以及3）定义 TSLP在体内诱导TH 2应答期间控制树突状细胞迁移的机制。

Project Summary/Abstract The skin is a barrier tissue with a large surface area in contact with the external environment and its own microbial flora. As such, immune responses in the skin must be tightly regulated to avoid unwanted and potentially harmful responses to innocuous environmental substances and commensal antigens, while allowing responses to a wide array of cutaneous pathogens. The consequences of dysregulated immune responses in the skin can be dire and include inflammatory diseases such as psoriasis, scleroderma and pemphigus vulgaris, as well as allergic responses that lead to acute and chronic atopic dermatitis (AD) and allergic contact dermatitis (ACD). We have shown that transgenic overexpression of the cytokine thymic stromal lymphopoietin (TSLP) specifically in the skin results in severe cutaneous inflammation resembling chronic AD. This inflammation is characterized by hyperactivation of CD4+ T cells and development of a strongly biased Th2 response, elevated serum levels of IgE, and severe dermal infiltration T cells, mast cells and eosinophils. Surprisingly, TSLP-overexpressing mice lacking T cells still develop the characteristic cutaneous inflammation, suggesting that myeloid cells are sufficient for the induction of TSLP-induced inflammation in the skin. The central hypotheses driving the experiments proposed in this study are that regulated expression of TSLP by keratinocytes activates resident myeloid cells in the skin, resulting in the induction of a cutaneous Th2 response and allergic inflammation in the skin. Strongly dysregulated TSLP expression in the skin causes myeloid cell hyperactivation, resulting in severe cutaneous immunopathology and development of strong Th2- mediated inflammation. To test these hypotheses and further define the role of TSLP in driving allergic inflammation, we will 1) Define the molecular pathways that lead to TSLP expression in the skin, 2) Determine the role of resident skin myeloid cells in initiating TSLP-mediated skin inflammation, and 3) Define the mechanisms by which TSLP controls dendritic cell migration during induction of TH2 responses in vivo.