Allergic Pulmonary Inflammation Through the Dectin-2 Pathway

描述（由申请人提供）：本申请旨在支持一项新的早期研究，重点关注Dectin-2在过敏原诱导的肺部炎症病理生理学中的作用。我们先前已经发现，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发现的聚糖激活，所述过敏原例如屋尘螨（HDM）物种粉尘螨（Dermatophagoides farinae）（Df）和屋尘螨（Dermatophagoides pteronyssinus）（Dp）以及霉菌烟曲霉（Aspergillus fumigatus）（Af）。Df、Dp或Af对Dectin-2的激活触发促炎细胞因子（IL-23、IL-1 β、IL-6和TNF-α）和半胱氨酰白三烯（cys-LT）的产生。由这种活化条件DC以自分泌方式产生的Cys-LTs通过半胱氨酰白三烯（cys-LTs）的1型受体CysLT1R促进Th2免疫应答。CysLT1R信号传导和DC上的Th2引发由cys-LTs的2型受体CysLT2R负调控。这些数据表明，Th2免疫过敏原可以精细调节信号从cys-LT。目前的提议将使用在经典和新型CysLTR中具有基因突变的小鼠品系来理解它们如何影响DC活化和Th2对天然过敏原的引发（Aim 1）。还将通过使用siRNA介导的CysLTR敲低来评估人单核细胞来源的DC。我们已经确定，Dectin-2在激发阶段期间在触发过敏性炎症中具有关键作用，并且当前提案的目标2将使用HDM致敏和激发的体内模型来理解Dectin-2和DC在激发阶段中的作用。超过50%的哮喘可归因于过敏，HDM是全球最常见的过敏原。因此，了解Dectin-2如何介导HDM触发的免疫病理学的致敏和传播提供了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.