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: 9753766
• 负责人: Daniel Fernando Camacho
• 金额: $ 5万
• 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/9753766
• 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; cytokine; effector T cell; experience; in vivo; inflammatory lung disease; insight; lymph nodes; 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.

项目总结/摘要 哮喘是一种慢性炎症性肺部疾病，每12个美国人中就有一个受到影响。大多数人 哮喘经历由吸入过敏原引发的2型肺部炎症。这种2型炎症， 其特征部分在于Th 2细胞和嗜酸性粒细胞增多，代表了对过敏原的适应性免疫应答。 最近，Th 17细胞反应也被描述在哮喘中，特别是在最严重的患者中。作为 获得性免疫主要由抗原呈递细胞如树突状细胞（DC）、肺DC（DC）和免疫球蛋白（IgG）协调。 在哮喘的发展中起着至关重要的作用。然而，分子机制如何 DC促进Th 2应答，而不是Th 17应答，仍然存在争议。我们集团和其他 已经确定IRF 4是肺DCs中启动2型炎症的关键转录因子。我们发现 两种不同的过敏原激活DC以上调转录因子IRF 4和下游细胞因子， IL-33和IL-10。重要的是，DCs中缺乏IRF 4的小鼠不会对HDM产生2型应答，这表明 IRF 4是启动2型炎症的肺DC中的关键转录因子。DC不需要IRF 4 在变应原暴露部位的肺组织中变应原的摄取。此外，IRF 4不是过敏原所必需的- 携带DC以到达肺引流淋巴结（LLN）。然而，早期T驻留内存响应是 当DC缺乏IRF 4时受损。这表明IRF 4是DC-T细胞相互作用所必需的。 导致Th 2指令或存储器规范。我的中心假设是，IRF 4是发展中国家所必需的， 在LLN中通过其下游效应分子如IL-33和IL-10的作用在Th 2启动期间。 为了解决我的假设，我建议确定1）DCs表达IRF 4的机制， 调节2型炎症和常驻记忆Th 2细胞的发育，以及2） 2型炎症和记忆反应中DC中IRF 4表达的下游效应物。 了解DC在哮喘期间促进炎症的机制对于哮喘的治疗至关重要。 开发新的治疗靶点。IRF 4或其下游效应分子是有吸引力的候选者 因为IRF 4（+）DC与Th 2和Th 17哮喘表型有关。通过 在这项研究中，我们试图揭示这些IRF 4（+）DCs是如何促进2型炎症的， 实验性哮喘的小鼠模型。