PGI2 regulation of TSLP-mediated allergic inflammation in the lung

描述（由申请人提供）：过敏性气道炎症是哮喘的标志，哮喘是美国发病的重要原因。第2组先天淋巴样细胞（ILC 2）产生细胞因子，驱动过敏性气道炎症的初始阶段。ILC 2被细胞因子如胸腺基质淋巴细胞生成素（TSLP）激活，所述细胞因子是响应于用链格孢菌（Alternaria alternata）的气道激发而产生的，链格孢菌是一种广泛存在的真菌空气过敏原，其与严重哮喘恶化有关。迄今为止，没有已知的肺ILC 2的负调节剂被FDA批准。然而，我们的新的初步数据表明，内源性PGI 2严重抑制气道TSLP的表达和肺表达的IL-5和IL-13，肺ILC 2表达的细胞因子，在用链格孢霉变应原提取物对小鼠进行气管内（IT）攻击后。额外的初步数据表明，外源性PGI 2抑制小鼠和人细胞中TSLP的先天免疫细胞表达。这些初步的数据使我们提出的假设，PGI 2负调节TSLP的表达和信号转导响应链格孢菌气道挑战，因此，抑制肺ILC 2的发展和功能。该提案将确定PGI 2如何调节宿主先天免疫细胞的激活以及导致过敏性炎症反应的链格孢菌中微生物抗原的信号传导途径。拟议的研究是范式转变，因为它们将确定PGI 2在阻断肺ILC 2表达IL-5和IL-13中的作用以及负责这种抑制的信号通路。这些拟议的研究具有临床相关性，因为我们将确定PGI 2（目前FDA批准用于治疗肺动脉高压）可能有效治疗过敏性气道炎性疾病（如哮喘）的潜在机制。此外，我们将确定如何饮食补充ω-3脂肪酸，减少内源性PGI 2，调节对链格孢菌攻击的早期先天性过敏性免疫反应。这种饮食已被推荐作为哮喘治疗，但我们的初步数据使我们假设ω-3脂肪酸饮食补充增加气道TSLP表达和肺ILC 2细胞细胞因子分泌，从而加剧过敏性气道炎症。拟议的研究将通过定义负调节对含蛋白酶的过敏原（如Alternaria alternata）的早期先天免疫应答的机制来推进该领域。

DESCRIPTION (provided by applicant): Allergic airway inflammation is a hallmark of asthma, a disease that is a significant cause of morbidity in the US. Group 2 innate lymphoid cells (ILC2) produce cytokines that drive the initial phase of allergic airway inflammation. ILC2 are activated by cytokines such as thymic stromal lymphopoietin (TSLP) that are produced in response to airway challenge with Alternaria alternata, a widespread fungal aeroallergen that has been linked to severe asthma exacerbations. To date, there are no known negative regulators of lung ILC2 that are approved by the FDA. However, our novel preliminary data reveals that endogenous PGI2 critically inhibits both airway TSLP expression and the lung expression of IL-5 and IL-13, cytokines expressed by lung ILC2, following intratracheal (IT) challenge of mice with the allergen extract of Alternaria alternata. Additional preliminary data suggests that exogenous PGI2 inhibits innate immune cell expression of TSLP in both mouse and human cells. These preliminary data lead us to propose the hypothesis that PGI2 negatively regulates the expression and signaling of TSLP in response to Alternaria airway challenge and, as a result, inhibits the development and function of lung ILC2. This proposal will determine how PGI2 regulates the activation of host innate immune cells and signaling pathways to the microbial antigens in Alternaria alternata that lead to allergic inflammatory responses. The proposed studies are paradigm shifting in that they will determine the role of PGI2 in blocking IL-5 and IL-13 expression by lung ILC2 and the signaling pathways responsible for this inhibition. These proposed studies are clinically relevant in that we will define potential mechanisms by which PGI2, which is currently FDA approved for the treatment of pulmonary hypertension, may be effective in the treatment of allergic airway inflammatory diseases such as asthma. In addition, we will define how dietary supplementation of ω-3 fatty acid, which reduces endogenous PGI2, regulates the early innate allergic immune response to Alternaria alternata challenge. Such diets have been recommended as asthma therapy, but our preliminary data leads us to hypothesize that ω-3 fatty acid dietary supplementation increases airway TSLP expression and lung ILC2 cell cytokine secretion, thus exacerbating allergic airway inflammation. The proposed studies will advance the field by defining mechanisms that negatively regulate the early innate immune response to the protease containing allergens such as Alternaria alternata.