Regulation of TSLP-Mediated Skin Inflammation

项目摘要/摘要 皮肤是一种具有较大表面积的屏障组织，与外部环境和自身接触 微生物区系。因此，必须严格控制皮肤的免疫反应，以避免不必要的和 对无害环境物质和共生抗原的潜在有害反应，同时允许 对多种皮肤病原体的反应。失调性免疫反应的后果 皮肤可能很可怕，包括牛皮癣、硬皮病和天疱疮等炎症性疾病。 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，转基因胸腺基质细胞因子过表达 淋巴生成素(TSLP)在皮肤中的特异性导致严重的皮肤炎，类似于慢性AD。 这种炎症的特点是CD4+T细胞过度激活和发展成强烈的偏向 Th2反应，血清IgE水平升高，真皮T细胞、肥大细胞和嗜酸性粒细胞严重浸润。 令人惊讶的是，缺乏T细胞的TSLP过度表达的小鼠仍然出现典型的皮肤炎， 提示髓系细胞足以诱导TSLP诱导的皮肤炎症。这个 推动这项研究中提出的实验的中心假设是TSLP通过 角质形成细胞激活皮肤中的常驻髓系细胞，导致皮肤Th2的诱导 皮肤的反应和过敏性炎症。皮肤中TSLP表达严重失调导致 髓系细胞过度激活，导致严重的皮肤免疫病理和强烈的Th2- 介导性炎症。检验这些假说，并进一步确定TSLP在驾驶过敏中的作用 炎症，我们将1)确定导致TSLP在皮肤中表达的分子途径，2)确定 常驻皮肤髓系细胞在启动TSLP介导的皮肤炎症中的作用，以及3)定义 TSLP在体内诱导TH2反应过程中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.