Regulation of TSLP-Mediated Skin Inflammation

描述（由申请人提供）：皮肤是一种屏障组织，具有与外部环境及其自身微生物植物群接触的大表面积。因此，必须严格调节皮肤中的免疫应答，以避免对无害环境物质和皮肤抗原的不想要的和潜在有害的应答，同时允许对广泛的皮肤病原体的应答。皮肤中失调的免疫应答的后果可能是可怕的，并且包括炎性疾病，如牛皮癣、硬皮病和寻常天疱疮，以及导致急性和慢性特应性皮炎（AD）和过敏性接触性皮炎（ACD）的过敏性应答。我们已经证明，细胞因子胸腺基质淋巴细胞生成素（TSLP）在皮肤中的转基因过表达会导致类似于慢性AD的严重皮肤炎症。这种炎症的特征在于CD4+ T细胞的过度活化和强烈偏向的Th2应答的发展、IgE的血清水平升高以及严重的皮肤浸润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特征性皮肤炎症，表明骨髓细胞足以诱导TSLP诱导的皮肤炎症。驱动本研究中提出的实验的中心假设是角质形成细胞对TSLP的调节表达激活皮肤中的常驻骨髓细胞，导致皮肤中皮肤Th2应答和过敏性炎症的诱导。皮肤中TSLP表达的强烈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Th2介导的炎症的发展。为了检验这些假设并进一步确定TSLP在驱动过敏性炎症中的作用，我们将1）确定导致TSLP在皮肤中表达的分子途径，2）确定驻留皮肤骨髓细胞在引发TSLP介导的皮肤炎症中的作用，和3）确定TSLP在体内诱导TH2应答期间控制树突状细胞迁移的机制。公共卫生相关性：特应性皮炎（AD）和变应性接触性皮炎（ACD）是常见的皮肤炎性疾病，其特征在于强烈瘙痒和慢性湿疹斑块，其通常与特应性的个人或家族史相关。这些疾病的病因和发病机制仍然很难确定。拟议的实验将有助于确定一种新的细胞因子，TSLP，在AD和ACD的诱导和进展的作用。这反过来将有助于指导开发针对这些和其他直接或间接靶向TSLP的皮肤炎性疾病的新干预措施。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are common inflammatory disease of the skin that are characterized by intense pruritus and chronic eczematous plaques that are often associated with a personal or family history of atopy. The etiology and pathogenesis of these diseases remain poorly characterized. The proposed experiments will help define the role of a novel cytokine, TSLP, in the induction and progression of AD and ACD. This in turn will help guide efforts to develop new interventions for these and other skin inflammatory diseases that directly or indirectly target TSLP.