Allergic Pulmonary Inflammation Through the Dectin-2 Pathway

描述（由申请人提供）：本申请旨在支持一个新的早期研究者，专注于Dectin-2在过敏原诱导的肺部炎症病理生理中的作用。我们之前已经发现树突状细胞（DC） c型凝集素受体Dectin-2被常见的临床相关过敏原中的聚糖激活，如屋尘螨（HDM）种Dermatophagoides farinae （Df）和Dermatophagoides pteronyssinus （Dp）和霉菌烟曲霉（Af）。Df、Dp或Af激活Dectin-2会触发促炎细胞因子（IL-23、IL-1 β、IL-6和TNF-¿）和半胱氨酸白三烯（cys- lt）的产生。这种激活条件下产生的cys- lt以自分泌方式通过半胱氨酸白三烯（cys- lt）的1型受体CysLT1R促进Th2免疫反应。CysLT1R信号通路和dc上的Th2启动受到CysLT2R的2型受体的负调控。这些数据表明，Th2对过敏原的免疫可以通过来自cys- lt的信号传导精细调节。目前的建议将使用具有经典和新型CysLTRs基因突变的小鼠品系来了解它们如何影响DC激活和Th2对天然过敏原的启动（Aim 1）。人类单核细胞来源的dc也将通过sirna介导的CysLTRs敲低进行评估。我们已经发现Dectin-2在激发阶段触发过敏性炎症中起关键作用，目前提案的Aim 2将使用HDM致敏和激发的体内模型来了解Dectin-2和DCs在激发阶段的作用。超过50%的哮喘可归因于过敏，而HDM是世界上最常见的过敏原。因此，了解Dectin-2如何介导hdm引发的免疫病理的致敏和传播提供了一个主要的潜在治疗益处。

DESCRIPTION (provided by applicant): This application to support a new early stage investigator focuses on the role of Dectin-2 in the pathophysiology of allergen-induced pulmonary inflammation. We have previously discovered that the dendritic cell (DC) C-type lectin receptor Dectin-2 is activated by glycans found in common, clinically relevant, allergens such as the house dust mite (HDM) species Dermatophagoides farinae (Df) and Dermatophagoides pteronyssinus (Dp) and the mold Aspergillus fumigatus (Af). Activation of Dectin-2 by Df, Dp, or Af triggers production of pro-inflammatory cytokines (IL-23, IL-1 beta, IL-6, and TNF-¿) and cysteinyl leukotrienes (cys- LTs). Cys-LTs produced by such activation condition DCs in an autocrine fashion to promote Th2 immune responses, via the type 1 receptor for cysteinyl leukotrienes (cys-LTs), CysLT1R. CysLT1R signaling and Th2 priming on DCs are negatively regulated by the type 2 receptor for cys-LTs, CysLT2R. These data suggest that Th2 immunity to allergens can be finely regulated by signaling from cys-LTs. The current proposal will use mouse strains with genetic mutations in classical and novel CysLTRs to understand how they influence DC activation and Th2 priming to native allergens (Aim 1). Human monocyte-derived DCs will also be assessed by using siRNA-mediated knockdown of CysLTRs. We have identified that Dectin-2 has a critical role in triggering allergic inflammation during the challenge phase and Aim 2 of the current proposal will use in vivo models of HDM sensitization and challenge to understand the role of Dectin-2 and DCs in the elicitation phase. Greater than 50% of asthma is attributable to allergy and HDM is the most common allergen worldwide. Therefore, understanding how Dectin-2 mediates sensitization and propagation of HDM-triggered immunopathology offers a MAJOR potential therapeutic benefit.