Role of pro- and anti-inflammatory NF-κB and MAPK signaling of innate dendritic cells during asthma development in childhood and its modulation through farm environmental exposure

本项目旨在解开儿童哮喘发展中免疫成熟过程中炎症调节（NF-κB和MAPK信号传导）的作用，以及通过环境刺激对其的保护。从两个出生队列和一个横断面队列的儿童的几个时间点采集血液样本，这些儿童有哮喘风险或受到保护，这为研究哮喘发展的免疫机制提供了一个独特的机会。免疫成熟过程中的促炎和抗炎通路以及如何调节这些通路以预防儿童哮喘的发生是两个重要的中心机制，由于NF-κB和MAPK信号传导是炎症的关键，我们将确定这些通路在健康免疫成熟的不同阶段中分离的树突状细胞（DC）中的特定作用，这对首次抗原接触很重要。此外，我们将剖析这些信号通路和树突状细胞亚群是否在儿童哮喘时受到不同的调节。我们将在几个阶段检查这些通路，即哮喘症状之前，早期症状阶段和哮喘慢性期。通过将最先进的机器学习算法应用于炎症和免疫成熟网络，我们的目标是确定它们是如何连接和调节在一起的。此外，我们的目标是用新的分析工具定义健康炎症和成熟的窗口。应用原理验证实验，我们旨在通过DC-T细胞共培养实验调节健康和哮喘儿童的炎症状态（在分离的DC中诱导促炎和抗炎状态），为了发展预防哮喘发展的概念，我们旨在解开一个新的概念，即训练免疫在环境介导的哮喘保护中的作用。为了实现这一目标，我们将研究先天免疫细胞的细胞特异性抗炎调节，研究转录机制的变化，并通过环境暴露研究表观遗传修饰。最后，我们的目标是确定一个“体内证据模型”，即评估炎症阈值和训练的免疫力。这个项目不仅将解开哮喘发展的促炎和抗炎机制，而且也代表了一个独特的机会，解剖机制如何环境介导的保护儿童哮喘可以实施。这对未来针对哮喘和可能的过敏的预防策略的转化研究至关重要。

This project aims to disentangle the role of inflammatory regulation (NF-κB and MAPK signalling) during immune maturation in childhood asthma development and its protection via environmental stimulation. Having blood samples from several time points of two birth cohorts and one cross-sectional cohort of children, which are at risk for asthma or protected from asthma offers a unique opportunity to examine immune mechanisms of asthma development. Two central mechanisms of interest are pro- and anti-inflammatory pathways during immune maturation and how these can be modulated in order to prevent the development of childhood asthma.As the two central pathways NF-κB and MAPK-signalling are key for inflammation, we will identify the specific role of these pathways in isolated dendritic cells (DC), important for first antigen-contact, at distinct stages of healthy immune maturation. Furthermore, we will dissect whether these signalling pathways and subpopulations of DCs are differently regulated when a child gets asthma. We will examine these pathways at several stages, namely prior to asthma symptoms, during the early symptomatic phase and during a chronic phase of asthma. By applying State-of-the-art machine learning algorithms for networks of inflammation and immune maturation, we aim to identify how they are connected and regulated together. Also, we aim to define a window of healthy inflammation and maturation with novel analysis tools. Applying a proof-of principle experiment, we aim to experimentally modulate inflammatory conditions (induction of pro- and anti- inflammatory conditions in isolated DC) of healthy and asthmatic children by DC-T-cell co-culture experiments.In order to develop preventive concepts for asthma development, we aim to disentangle the role of a novel conception named trained immunity in environment-mediated asthma protection. To achieve this, we will examine cell-specific anti-inflammatory regulation of innate immune cells, investigate changes in the transcriptional machinery and examine epigenetic modification via environmental exposure. Finally, we aim to identify a “model of in vivo proof”, namely to assess an inflammatory threshold and trained immunity.This project will not only disentangle pro- and anti-inflammatory mechanisms of asthma development, but also represents a unique opportunity to dissect mechanisms how environment-mediated protection against childhood asthma can be implemented. This is critical for future translational studies for preventive strategies against asthma and possibly allergies.