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.

项目概要/摘要 哮喘是一种慢性炎症性肺部疾病，每十二名美国人中就有一人患有哮喘。大多数人有 哮喘患者会因吸入过敏原而引发 2 型肺部炎症。这种2型炎症， 部分特征为 Th2 细胞和嗜酸性粒细胞增多，代表对过敏原的适应性免疫反应。 最近，Th17 细胞反应也被描述在哮喘中，尤其是在最严重的患者中。作为 适应性免疫主要由树突状细胞 (DC)、肺 DC 等抗原呈递细胞协调 被认为是哮喘发展的关键因素。然而，其分子机制如何 DCs 促进 Th2 反应，而不是 Th17 反应，仍然存在争议。我们组和其他人 已确定 IRF4 是肺 DC 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 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 中缺乏 IRF4 的小鼠不会对 HDM 产生 2 型反应，这表明 IRF4 是肺 DC 中引发 2 型炎症的关键转录因子。 DC 不需要 IRF4 过敏原暴露部位的肺组织吸收过敏原。此外，IRF4 不是过敏原所必需的。 携带 DC 到达肺引流淋巴结 (LLN)。然而，早期 T 驻留记忆反应是 当 DC 缺乏 IRF4 时，其功能就会受到损害。这表明 IRF4 是 DC-T 细胞相互作用所必需的 产生 Th2 指令或内存规范。我的中心假设是 DC 需要 IRF4 在 Th2 启动过程中，通过其下游效应分子（例如 LLN 中的 IL-33 和 IL-10）的作用。 为了验证我的假设，我建议确定 1) DC 表达 IRF4 的机制 调节 2 型炎症和常驻记忆 Th2 细胞的发育，2) 的作用 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于治疗哮喘至关重要。 开发新的治疗靶点。 IRF4 或其下游效应分子是有吸引力的候选者 为此目的，因为 IRF4(+) DCs 与 Th2 和 Th17 哮喘表型有关。通过 在拟议的研究中，我们试图揭示这些 IRF4(+) DCs 如何发挥作用来促进 2 型炎症 实验性哮喘小鼠模型。