IRF4+ respiratory dendritic cells in type 2 inflammatory responses

IRF4呼吸树突状细胞在2型炎症反应中的作用

• 批准号: 9311817
• 负责人: Anne I. Sperling
• 金额: $ 39.72万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-06 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9311817
• 关键词: Address; Affect; Allergens; Allergic; Antigen-Antibody Complex; Antigen-Presenting Cells; Asthma; Automobile Driving; Basic Science; Bone Marrow; Breathing; Cell physiology; Cell surface; Cells; Characteristics; Child; Clinical Medicine; Data; Defect; Dendritic Cells; Development; Disease; Experimental Models; Goals; Human; Hypersensitivity; IRF4 gene; ITGAM gene; ITGAX gene; Individual; Inflammation; Inflammatory Response; Interleukin-10; Knock-out; Lung; Mediator of activation protein; Memory; Molecular; Mus; Pathogenesis; Patients; Phenotype; Play; Population; Precipitating Factors; Prevalence; Production; Pyroglyphidae; RNA analysis; Regulation; Research; Role; Severities; Signal Transduction; Stimulus; T memory cell; T-Lymphocyte; TSLP gene; Testing; Th2 Cells; Therapeutic Intervention; Tissues; United States; Up-Regulation; asthmatic; cytokine; in vivo; memory recall; migration; monocyte; mouse model; new therapeutic target; receptor; respiratory; response; transcription factor; transcriptome sequencing; translational study

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.

项目摘要 哮喘和过敏会影响全球估计的2.35亿人，代表了一个重要的挑战 基础科学使临床医学受益。儿童是哮喘和越来越多的人口 GY患者，但尚不清楚降水因素。我们目前对这些疾病恶魔的理解 - 表明Th2细胞在这些疾病的2型炎症反应特征中起主要作用。 最近，TH17细胞反应也与哮喘有关，尤其是最严重的患者。 然而，影响T细胞分化为Th2表型的因素，而不是Th17表型， 仍然是这些疾病中重要的未解决问题之一。树突状细胞（DC）是抗原 呈现诱导Th2分化的中心的细胞。但是，分子机制 Th2扭动DC（DCTH2）的发展仍然存在争议。通过我们小组和其他人的研究 转录因子IRF4已成为DCTH2开发的关键调节剂。我们发现两个不同的al- Lergic Stimulli，免疫复合物和房屋粉尘提取物（HDM）可以通过FCRγ相关的重新发出信号 诱导骨髓衍生的DC（BMDC）更新IRF4的CEPTOR，并且IRF4表达是必需的 SARY用于BMDC的细胞因子IL-33和IL-10的生产。此外，HDM诱导的2型注射 在CD11C+ DC中缺乏IRF4表达的小鼠中，TH2反应减少了。在一起，这些数据 确定通过DC上通过FCRγ相关受体信号的Th2刺激来诱导IRF4的机制 表达以及IL-33和IL-10产生。但是，IRF4的DC表达的体内机制 促进2型炎症，这些研究与人类哮喘的相关性仍然未知。 该项目的总体假设是，通过上调IRF4及其下游介体DCS 诱导2型感染和组织居民记忆（TRM）TH2细胞的发展 具有实验性哮喘的哮喘患者和小鼠。为了解决我们的假设，我们建议确定1） DC通过DC调节2型注射和居民的发展的机制 记忆Th2细胞，2）IRF4表达在DC中的下游效应在2型注射和 记忆反应，以及3）人类肺DC的IRF4表达是否受哮喘状态和 哮喘细胞因子环境。了解DC促进哮喘型炎症的机制是 开发新目标的关键。 IRF4或其下游效应子分子是吸引人的 出于此目的，候选者由于IRF4+ DC在TH2和TH17哮喘势中均暗示 类型。通过拟议的翻译研究，我们试图揭示这些IRF4+ DC如何促进 实验性哮喘和人哮喘的小鼠模型中的2型炎症。