Regulation of TSLP-Mediated Skin Inflammation

TSLP 介导的皮肤炎症的调节

• 批准号: 8061690
• 负责人: Daniel J Campbell
• 金额: $ 39.13万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8061690
• 关键词: Acute; Address; Allergic Contact Dermatitis; Allergic inflammation; Antigens; Area; Atopic Dermatitis; Automobile Driving; CD4 Positive T Lymphocytes; Characteristics; Chronic; Cutaneous; Dendritic Cells; Dermal; Development; Disease; Environment; Etiology; Family history of; Health; IgE; Immune response; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Intervention; Lead; Mediating; Molecular; Mus; Myeloid Cells; Pathogenesis; Pathway interactions; Pemphigus Vulgaris; Population; Pruritus; Psoriasis; Regulation; Role; Scleroderma; Serum; Skin; Surface; T-Cell Development; T-Lymphocyte; Testing; Th2 Cells; Tissues; Transgenic Organisms; allergic response; atopy; cell motility; cytokine; eosinophil; human TSLP protein; immunopathology; in vivo; keratinocyte; lymph nodes; macrophage; mast cell; microbial; migration; novel; overexpression; pathogen; research study; response; skin disorder

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.

描述（由申请人提供）：皮肤是屏障组织，表面积很大，与外部环境及其自身微生物菌群接触。因此，必须严格调节皮肤中的免疫反应，以避免对无害环境物质和共同抗原的不必要的和潜在的有害反应，同时允许对各种皮肤病的反应。皮肤中免疫反应失调的后果可能是可怕的，包括牛皮癣，硬皮病和pemphigus vulgaris等炎症性疾病，以及导致急性和慢性性感性皮肤炎（AD）和过敏性触及性触点性接触性触及性皮肤炎（ACD）的过敏反应（ACD）。我们已经表明，在皮肤中，细胞因子胸腺基质淋巴结蛋白（TSLP）的转基因过表达在皮肤上会导致类似于慢性AD的严重皮肤炎症。这种炎症的特征是CD4+ T细胞过度激活以及偏见的Th2反应，血清水平升高，精神真皮浸润T细胞，肥大细胞和嗜酸性粒细胞的升高。令人惊讶的是，缺乏TSLP表达TSLP的小鼠仍然会发展出特征性的皮肤炎症，这表明髓样细胞足以诱导TSLP诱导的皮肤炎症。这项研究中提出的实验的中心假设是，角质形成细胞调节TSLP的表达会激活皮肤中常驻的髓样细胞，从而导致皮肤皮肤TH2反应和过敏性炎症诱导。皮肤中TSLP表达强烈失调会导致髓样细胞过度激活，导致严重的皮肤免疫病理学和强烈TH2-介导的炎症的发展。 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.公共卫生相关性：特应性皮炎（AD）和过敏性接触性皮炎（ACD）是皮肤的常见炎症性疾病，其特征在于瘙痒和慢性湿疹斑块，通常与特应特亚西的个人或家族史有关。这些疾病的病因和发病机理的特征仍然很差。提出的实验将有助于定义新型细胞因子TSLP在AD和ACD的诱导和进展中的作用。反过来，这将有助于指导为直接或间接针对TSLP的这些皮肤炎症性疾病开发新的干预措施。