IRF4+ respiratory dendritic cells in type 2 inflammatory responses

项目摘要/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。大多数患有此病的人 哮喘经历由吸入变应原引发的2型肺部炎症。这种2型炎症， 部分以Th2细胞和嗜酸性粒细胞为特征，代表对过敏原的适应性免疫反应。 最近，Th17细胞反应在哮喘中也被描述出来，特别是在最严重的患者中。AS 获得性免疫主要由抗原提呈细胞如树突状细胞(DC)、肺DC 在哮喘的发展过程中起着至关重要的作用。然而，分子机制是如何 DC促进Th2应答，而不是Th17应答，仍然存在争议。我们的团队和其他人 已确定IRF4是启动2型炎症的肺树突状细胞中的关键转录因子。我们发现了 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。关键的是，DC中缺乏IRF4的小鼠不会对HDM产生2型反应，这表明 IRF4是肺树突状细胞中的一个关键转录因子，可启动2型炎症。DC不需要IRF4 过敏原暴露部位肺组织中的过敏原摄取。此外，IRF4不是过敏原所必需的- 载树突状细胞到达肺引流的淋巴结节(11n)。然而，早期T驻留内存响应是 当DC缺乏IRF4时受损。这表明IRF4是DC-T细胞相互作用所必需的 从而产生TH2指令或存储器规范。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如IL-33和IL-10在LN中的作用。 为了解决我的假设，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细胞的发展和2)的作用 IRF4在DC中表达的下游效应因子在2型炎症和记忆反应中的作用。 了解DC在哮喘过程中促进炎症的机制对于 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，由于IRF4(+)树突状细胞与Th2和Th17哮喘表型有关。穿过 在这项拟议的研究中，我们试图揭示这些IRF4(+)DC如何在促进2型炎症中发挥作用 实验性哮喘的小鼠模型。

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.