Components of distinct rural environments confer asthma protection in childhood via A20-mediated immune effects in dendritic cells on regulatory T cells

点击翻译按钮获取中文摘要

This project aims to disentangle distinct protective immune regulatory mechanisms of A20-mediated effects of dendritic (DC) and regulatory T cells (Tregs) for childhood asthma by stimulation of blood cells with compounds of environmentally distinct areas. The unique natural exposure to two environments strongly protecting from childhood asthma, i.e. farms in Europe and rural areas in China offers the great opportunity to assess underlying immune mechanisms which are distinct from each other. As A20 (anti-inflammatory) and inflammasome regulation have been shown differentially expressed following different dust stimulation, we will identify the specific role of A20 and inflammasome regulation following environmental exposure with different dusts in cell lines, and isolated cells. We will disentangle specific asthma-protective immune mechanisms via A20-mediated effects of DCs on Tregs through exposure to distinct rural environmental dust in healthy and asthmatic children. We will unravel the effect of environmental dust extracts from different environmental areas (Germany, Finland, China) on T reg-function, methylation, acetylation (FOXP3 promoter), and mTOR signalling. We aim to identify signalling of A20 regulation in DCs and inflammasome activation. We aim to investigate the effect of A20-regulation in DCs and inflammasome activation on Treg-mediated suppression. Finally, in a proof-of-principle experiment, we will assess the effects of dust stimulation on A20-regulation in DCs, inflammasome and Treg regulation in children protected from asthma in comparison to asthmatic children. Different metabolites of microbial bacteria such as short-chain fatty acids (SCFA) have been shown critical for Treg-function protecting against murine colitis, and possibly murine allergic airway inflammation. Thus, we aim to identify the effect of SCFA (and other metabolites of dust of distinct environmental areas) on the regulation of the A20-mediated DC-Treg-axis and inflammasome regulation for asthma protection. To pin-point the relevant components, we will examine the content of SCFA and metabolites present in the different dusts. We aim to investigate the effects of SCFA on DC and Treg-responses in vitro in protected and asthmatic children. We are now in the unique position of i) having the dusts from distinct rural environments available in sufficient amount and quality, ii) having a comparison of children at risk and protected from asthma in different cohorts available to comprehensively assess A20-mediated DC-Treg mechanisms for subsequent strategies for primary/secondary prevention of childhood asthma. This project will not only provide in depth pathway analysis of relevant factors for asthma protection, but represents an unparalleled opportunity to disentangle different or common pathways in environmentally very distinct areas (Europe/China), which is critical for the translation into future prevention strategies for childhood asthma.