IRF4+ respiratory dendritic cells in type 2 inflammatory responses

项目摘要 哮喘和过敏症影响着全球约2.35亿人，是一个重要的挑战。 为基础科学造福临床医学。儿童是哮喘的主要和不断增长的人群， 戈伊障碍患者，但促发因素尚不清楚。我们目前对这些疾病的了解- 表明Th 2细胞在这些疾病的2型炎症反应特征中起主要作用。 最近，Th 17细胞反应也与哮喘有关，特别是在最严重的患者中。 然而，诱导T细胞向Th 2表型而不是Th 17表型分化的因子， 仍然是这些疾病中尚未解决的重要问题之一。树突状细胞（DC）是抗原- 提呈细胞对诱导Th 2分化至关重要。然而， Th 2-skewing DCs（DCTh 2）的发育一直存在争议。通过我们小组和其他人的研究， 转录因子IRF 4已经成为DCTh 2发育的关键调节因子。我们发现两种不同的铝- 过敏性刺激物，免疫复合物和屋尘螨提取物（HDM），可以通过FcRγ相关的再活化信号传导， 受体诱导骨髓来源的DC（BMDC）上调IRF 4，IRF 4的表达是必要的。 BMDC产生细胞因子IL-33和IL-10的条件。此外，HDM诱导的2型炎症 在CD 11 c + DC中缺乏IRF 4表达的小鼠中，Th 2应答降低。这些数据一起 鉴定Th 2刺激通过DC上FcRγ相关受体信号传导以诱导IRF 4的机制 表达和IL-33和IL-10产生。然而，DC表达IRF 4的体内机制 促进2型炎症，这些研究与人类哮喘的相关性仍然未知。的 该项目的总体假设是，通过上调IRF 4及其下游介质， 诱导肺中2型炎症和组织驻留记忆（TRM）Th 2细胞的发展， 哮喘患者和实验性哮喘小鼠。为了解决我们的假设，我们建议确定1） DCs表达IRF 4调节2型炎症和驻留细胞发生的机制 记忆性Th 2细胞，2）DC中IRF 4表达的下游效应物在2型炎症中的作用， 记忆反应，以及3）人肺DCs的IRF 4表达是否受哮喘状态的影响， 哮喘细胞因子环境。了解树突状细胞促进哮喘型炎症的机制， 开发新的治疗靶点的关键。IRF 4或其下游效应分子是吸引- 由于IRF 4 + DCs与Th 2和Th 17哮喘表型有关， 类型通过所提出的翻译研究，我们试图揭示这些IRF 4 + DC如何发挥功能以促进 在实验性哮喘小鼠模型和人类哮喘中的2型炎症。

PROJECT SUMMARY Asthma and allergies affect an estimated 235 million people worldwide and represent an important challenge for basic science to benefit clinical medicine. Children are a major and growing population of asthma and aller- gy sufferers, but the precipitating factors are not known. Our current understanding of these diseases demon- strates that Th2 cells play a major role in the type 2 inflammatory response characteristic of these diseases. Recently, Th17 cell responses have also been implicated in asthma, especially in the most severe patients. However, the factors that induce T cells to differentiate towards a Th2 phenotype, and not a Th17 phenotype, remain one of the important unresolved problems in these diseases. Dendritic cells (DCs) are antigen- presenting cells central to the induction of Th2 differentiation. However the molecular mechanisms by which Th2-skewing DCs (DCTh2) develop has remained controversial. Through studies by our group and others, the transcription factor IRF4 has emerged as a key regulator of DCTh2 development. We found that two distinct al- lergic stimuli, immune complexes and house dust mite extract (HDM), can signal through FcRγ-associated re- ceptors to induce bone marrow-derived DCs (BMDC) to upregulate IRF4, and that IRF4 expression is neces- sary for the BMDCs production of the cytokines IL-33 and IL-10. Further, HDM-induced type 2 inflammation and Th2 responses are reduced in mice lacking expression of IRF4 in CD11c+ DCs. Together, these data identify a mechanism whereby Th2 stimuli signal through FcRγ-associated receptors on DCs to induce IRF4 expression and IL-33 and IL-10 production. However, the in vivo mechanisms by which DC expression of IRF4 promotes type 2 inflammation, and the relevance of these studies to human asthma, remain unknown. The overall hypothesis of this project is that through the upregulation of IRF4 and its downstream mediators, DCs induce the development of type 2 inflammation and tissue resident memory (TRM) Th2 cells in the lungs of asthmatics and mice with experimental asthma. To address our hypothesis, we propose to determine 1) the mechanisms by which IRF4 expression by DCs regulate type 2 inflammation and the development of resident memory Th2 cells, 2) the role of downstream effectors of IRF4 expression in DCs in type 2 inflammation and memory responses, and 3) whether IRF4 expression by human lung DCs is affected by asthma status and the asthmatic cytokine milieu. Understanding the mechanisms by which DCs promote asthma-type inflammation is key to the development of new targets for therapeutics. IRF4, or its downstream effector molecules, are attrac- tive candidates for this purpose since IRF4+ DCs have been implicated in both Th2 and Th17 asthma pheno- types. Through the proposed translational study, we seek to reveal how these IRF4+ DCs function to promote type 2 inflammation in mouse models of experimental asthma and in human asthma.