Allergic Pulmonary Inflammation Through the Dectin-2 Pathway

这个应用程序支持一个新的早期研究人员，重点是Dectin-2在 变应原所致肺部炎症的病理生理学。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、临床相关的、 过敏原，如屋尘螨(HDM)、粉尘螨(DF)和粉尘螨 Pteronyssinus(DP)和霉菌Aspergillusfumigatus(Af)。Df、Dp或Af触发器激活Dectin-2 产生促炎细胞因子(IL-23、IL-1β、IL-6和TNF-β)和半胱氨酰白三烯(Cys-1)。 它)。由这种激活条件下的DC以自分泌方式产生的Cys-LT促进Th2免疫 通过半胱氨酰白三烯1型受体(Cys-LTS)，CysLT1R。CysLT1R信号与Th2 DC的启动受Cys-LTs的2型受体CysLT2R的负调控。这些数据表明 Th2对过敏原的免疫可以通过Cys-Lts的信号进行精细调节。目前的提案将使用 具有经典和新型CysLTRs基因突变的小鼠品系了解它们如何影响DC 对本地变应原的激活和Th2启动(目标1)。人类单核细胞来源的树突状细胞也将被评估 通过siRNA介导的CysLTRs敲除。我们已经确定Dectin-2在 在挑战阶段触发过敏性炎症，目前提案的目标2将在体内使用 HDM的致敏模型和挑战，以了解Dectin-2和DC在诱导阶段的作用。 超过50%的哮喘可归因于过敏，而HDM是全球最常见的过敏原。 因此，了解Dectin-2如何介导HDM触发的敏化和传播 免疫病理学提供了一个主要的潜在的治疗益处。

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.