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.

项目总结 据估计，全球有2.35亿人患有哮喘和过敏，这是一项重要的挑战 让基础科学造福临床医学。儿童是哮喘的主要人群，而且还在不断增长。 患者，但诱发因素尚不清楚。我们目前对这些疾病的理解是恶魔- 研究表明，Th2细胞在这些疾病的2型炎症反应中起主要作用。 最近，Th17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细胞分化为Th2表型而不是Th17表型的因素， 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)是一种抗原- 提出了诱导Th2分化的中心细胞。然而，其分子机制 Th2偏斜DC(DCTh2)的发展一直存在争议。通过我们小组和其他人的研究， 转录因子IRF4已成为DCTh2发育的关键调控因子。我们发现两个截然不同的al- 过敏刺激、免疫复合体和屋尘螨提取物可以通过fcrγ相关的Re-1传递信号。 受体诱导骨髓源性DC(BMDC)上调IRF4，IRF4的表达是必要的。 骨髓基质细胞产生细胞因子IL-33和IL-10的研究。此外，HDM诱导的2型炎症 在CD11c+DC中缺乏IRF4表达的小鼠Th2应答减少。总而言之，这些数据 确定Th2通过树突状细胞上的FCRIRF4相关受体发出信号来诱导γ的机制 表达及IL-33、IL-10的产生。然而，DC表达IRF4的体内机制 促进2型炎症，以及这些研究与人类哮喘的相关性仍不清楚。这个 该项目的总体假设是，通过上调IRF4及其下游介体，DC 诱导小鼠肺组织II型炎症和组织驻留记忆(TRM)Th2细胞的形成 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) 树突状细胞表达IRF4调节2型炎症和居民发病的机制 记忆Th2细胞，2)树突状细胞中IRF4表达的下游效应因子在2型炎症和 记忆反应，以及3)人肺树突状细胞IRF4的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 是开发新的治疗靶点的关键。IRF4，或其下游效应分子，被吸引- 由于IRF4+DC与Th2和Th17哮喘表型有关，因此有可能达到这一目的。 类型。通过拟议的翻译研究，我们试图揭示这些IRF4+DC如何发挥促进作用 实验性哮喘小鼠模型和人类哮喘模型中的2型炎症。