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: 10078845
• 负责人: Julian Solway
• 金额: $ 39.9万
• 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/10078845
• 关键词: Address; Affect; Allergens; Allergic; Antigen-Antibody Complex; Antigen-Presenting Cells; Asthma; Automobile Driving; Basic Science; Bone Marrow; 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; Inhalation; 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.

项目概要 哮喘和过敏影响着全球约 2.35 亿人，是一项重要的挑战 基础科学有益于临床医学 儿童是哮喘和过敏症的主要且不断增长的人群。 gy 患者，但我们目前对这些疾病的了解尚不清楚。 表明 Th2 细胞在这些疾病特有的 2 型炎症反应中发挥着重要作用。 最近，Th17 细胞反应也与哮喘有关，尤其是在最严重的患者中。 然而，诱导 T 细胞分化为 Th2 表型而非 Th17 表型的因素， 树突状细胞（DC）的抗原仍然是这些疾病中尚未解决的重要问题之一。 然而，细胞对 Th2 分化的诱导至关重要。 通过我们小组和其他人的研究，Th2 倾斜 DC（DCTh2）的发展仍然存在争议。 转录因子 IRF4 已成为 DCTh2 发育的关键调节因子，我们发现两个不同的蛋白。 过敏刺激、免疫复合物和屋尘螨提取物 (HDM)，可以通过 FcRγ 相关的重新信号传递信号 受体诱导骨髓源性树突状细胞 (BMDC) 上调 IRF4，并且 IRF4 表达是必要的- BMDC 产生细胞因子 IL-33 和 IL-10 此外，HDM 诱导的 2 型炎症也有类似作用。 这些数据表明，在 CD11c+ DC 中缺乏 IRF4 表达的小鼠中，Th2 反应降低。 确定 Th2 刺激信号通过 DC 上的 FcRγ 相关受体诱导 IRF4 的机制 然而，DC 表达 IRF4 的体内机制。 促进 2 型炎症，而这些研究与人类哮喘的相关性仍不清楚。 该项目的总体假设是，通过上调 IRF4 及其下游介质，DC 诱导肺部 2 型炎症和组织驻留记忆 (TRM) Th2 细胞的发展 为了解决我们的假设，我们建议确定 1) 哮喘患者和患有实验性哮喘的小鼠。 DC 表达 IRF4 调节 2 型炎症和常驻炎症发展的机制 记忆 Th2 细胞，2) DC 中 IRF4 表达的下游效应子在 2 型炎症和 记忆反应，3) 人肺 DC 的 IRF4 表达是否受哮喘状态和哮喘状态的影响 了解 DC 促进哮喘型炎症的机制是很重要的。 IRF4或其下游效应分子的开发新靶点的关键是有吸引力的。 由于 IRF4+ DC 与 Th2 和 Th17 哮喘表型有关，因此成为了用于此目的的候选药物。 通过拟议的转化研究，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中的 2 型炎症。