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: 9981798
• 负责人: Daniel Fernando Camacho
• 金额: $ 5.05万
• 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: 2017-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981798
• 关键词: Activities of Daily Living; Address; Affect; Allergens; Allergic; American; Antigen-Presenting Cells; Asthma; Back; Cell Communication; Cell physiology; Cells; Chronic; Data; Defect; Dendritic Cells; Development; Disease; Eosinophilia; Experimental Models; Fellowship; Goals; IRF4 gene; ITGAM gene; Immune; Immunologist; Impairment; Inflammation; Inflammatory Response; Inhalation; Instruction; Interleukin-10; Interleukin-13; Interleukin-4; Interleukin-5; Knockout Mice; Lung; Lung Inflammation; Memory; Molecular; Mouse Strains; Mus; Pathogenesis; Patients; Phenotype; Physicians; Prevalence; Production; Pyroglyphidae; Regulation; Research; Role; Scientist; Severities; Site; Structure of parenchyma of lung; T cell response; T memory cell; T-Lymphocyte; Testing; Th2 Cells; Therapeutic Intervention; Training; United States; adaptive immune response; adaptive immunity; asthmatic; conditional knockout; cytokine; draining lymph node; effector T cell; experience; in vivo; inflammatory lung disease; insight; migration; mouse model; new therapeutic target; novel; recruit; respiratory; response; therapeutic target; tool; transcription factor; transcriptome sequencing; translational impact; uptake

PROJECT SUMMARY/ABSTRACT Asthma is a chronic inflammatory lung disease that affects one in every twelve Americans. Most people with asthma experience type 2 lung inflammation triggered by the inhalation of allergens. This type 2 inflammation, characterized in part by Th2 cells and eosinophilia, represents an adaptive immune response to allergens. Recently, Th17 cell responses have also been described in asthma, especially in the most severe patients. As adaptive immunity is principally orchestrated by antigen presenting cells like dendritic cells (DCs), lung DCs are implicated as crucial players in the development of asthma. However, the molecular mechanisms of how DCs promote Th2 responses, as opposed to Th17 responses, remain controversial. Our group and others have identified IRF4 as a key transcription factor in lung DCs that initiate type 2 inflammation. We have found that two distinct allergens activate DCs to upregulate the transcription factor IRF4 and downstream cytokines IL-33 and IL-10. Critically, mice lacking IRF4 in DCs do not develop type 2 responses to HDM, suggesting that IRF4 is a key transcription factor in lung DCs that initiate type 2 inflammation. IRF4 is not required for DC uptake of allergen in the lung tissue at the site of allergen exposure. Further, IRF4 is not required for allergen- bearing DCs to reach the lung-draining lymph nodes (LLN). However, early T resident memory responses are impaired when DCs are deficient in IRF4. This suggests that IRF4 is required for DC-T cell interactions resulting in Th2 instruction or memory specification. My central hypothesis is that IRF4 is required in DCs during Th2 initiation via the actions of its downstream effector molecules such as IL-33 and IL-10 in the LLN. To address my hypothesis, I propose to determine 1) the mechanisms by which IRF4 expression by DCs regulates type 2 inflammation and the development of resident memory Th2 cells and 2) the role of downstream effectors of IRF4 expression in DCs in type 2 inflammation and memory responses. Understanding the mechanisms by which DCs promote inflammation during asthma is critical to the development of new therapeutic targets. IRF4, or its downstream effector molecules, are attractive candidates for this purpose since IRF4(+) DCs have been implicated in both Th2 and Th17 asthma phenotypes. Through the proposed study, we seek to reveal how these IRF4(+) DCs function to promote type 2 inflammation in mouse models of experimental asthma.

项目摘要/摘要 哮喘是一种慢性炎症性肺部疾病，每十二个美国人都会影响一种。大多数人 哮喘体验2型肺部炎症是由过敏原吸入引发的。这种2型炎症， Th2细胞和嗜酸性粒细胞的一部分表征，代表对过敏原的适应性免疫反应。 最近，哮喘中也描述了Th17细胞反应，尤其是在最严重的患者中。作为 自适应免疫主要由抗原呈现的细胞（如树突状细胞）（DCS），肺DC策划 在哮喘的发展中被认为是至关重要的参与者。但是，如何 与TH17反应相反，DC促进了TH2反应，这仍然存在争议。我们的小组和其他人 已将IRF4确定为启动2型炎症的肺DC中的关键转录因子。我们找到了 两种不同的过敏原激活DC，以上调转录因子IRF4和下游细胞因子 IL-33和IL-10。至关重要的是，DC中缺少IRF4的小鼠不会对HDM产生2型的反应，这表明 IRF4是引发2型炎症的肺DC中的关键转录因子。 DC不需要IRF4 在过敏原暴露部位的肺组织中摄取过敏原。此外，过敏原不需要IRF4 轴承直流达到肺淋巴结（LLN）。但是，早期的常驻记忆响应是 当DC缺乏IRF4时会受到损害。这表明DC-T细胞相互作用需要IRF4 导致TH2指令或内存规范。我的中心假设是DC中需要IRF4 在Th2开始，通过其下游效应分子的作用（例如LLN中的IL-33和IL-10）的作用。 为了解决我的假设，我建议确定1）DCS表达IRF4的机制 调节2型炎症和居民记忆Th2细胞的发展，2） DC在2型炎症和记忆反应中DC中IRF4表达的下游效应子。 了解DC在哮喘期间促进炎症的机制对 开发新的治疗靶标。 IRF4或其下游效应子分子是有吸引力的候选者 为此，由于IRF4（+）DC都与Th2和Th17哮喘表型有关。通过 拟议的研究，我们试图揭示这些IRF4（+）DC的功能如何促进2型炎症 实验性哮喘的小鼠模型。