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

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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.