PGI2 regulation of TSLP-mediated allergic inflammation in the lung

描述(由申请人提供)：过敏性呼吸道炎症是哮喘的一个标志，哮喘是美国发病率的重要原因。第二组先天淋巴样细胞(ILC2)产生细胞因子，驱动过敏性呼吸道炎症的初始阶段。ILC2由细胞因子激活，如胸腺基质淋巴生成素(TSLP)，这些细胞因子是对互隔交链孢霉(Alternaria Alternata)的呼吸道攻击做出反应而产生的，交链孢霉是一种广泛存在的真菌空气变应原，与严重的哮喘恶化有关。到目前为止，还没有已知的肺ILC2负性调节剂得到FDA的批准。然而，我们新的初步数据显示，内源性PGI2严重抑制了小鼠呼吸道TSLP的表达和肺IL-5和IL-13的表达，IL-5和IL-13是由肺ILC2表达的细胞因子，在小鼠气管内用互隔交链孢变应原提取物攻击后。更多的初步数据表明，外源性PGI2抑制了小鼠和人类细胞中TSLP的天然免疫细胞表达。这些初步数据使我们提出假设，即PGI2负性调节TSLP的表达和信号转导，以响应交链孢霉的呼吸道攻击，从而抑制肺ILC2的发育和功能。这一建议将确定PGI2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微生物抗原的信号通路。所提出的研究是范式的转变，因为他们将确定PGI2在通过肺ILC2阻断IL-5和IL-13表达方面的作用以及导致这种抑制的信号通路。这些拟议的研究具有临床意义，因为我们将确定目前FDA批准用于治疗肺动脉高压的PGI2可能有效治疗过敏性呼吸道炎症疾病(如哮喘)的潜在机制。此外，我们将确定饮食补充ω-3脂肪酸如何调节对互隔交链孢菌挑战的早期先天过敏免疫反应。这种饮食被推荐作为哮喘的治疗方法，但我们的初步数据使我们假设，ω-3脂肪酸饮食补充增加了气道TSLP的表达和肺ILC2细胞细胞因子的分泌，从而加剧了过敏性气道炎症。拟议的研究将通过定义负面调节对含有蛋白酶的过敏原(如交链格孢菌)的早期先天免疫反应的机制来推动该领域的发展。

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.