Potential drivers of the atopic march - unraveling the skin-lung crosstalk

Abstract

Atopic diseases such as atopic dermatitis (AD), food allergy, allergic rhinitis, and allergic asthma are not only an economical burden to the healthcare system but also a highly physiological and psychological burden for patients. Similar pathophysiological patterns like increased IgE plasma concentration as well as Th2-dominant inflammation characterize these diseases. By now, it is well-accepted that AD is the “entry point“ for a successive development of further atopic diseases during the first 10 years of life - a process known as the atopic march. However, the underlying mechanisms are still not fully understood and by far not all responsible factors have been identified; a drawback resulting in poor options for prevention. In this thesis, a human-based two-organ co-culture of skin disease equivalents, mimicking hallmarks of AD, and healthy bronchial epithelial equivalents was established for studying the pathophysiological crosstalk between skin and bronchi. Already a short co-cultivation period of six days induced a clear hyperproliferative phenotype with elevated mucus-secretion and an increase of inflammatory markers as determined on gene and protein level. Consequently, this led to the suggestion that either epithelial or dermal factors might play a role due to missing immune cells in this co-culture. Secretome of skin disease equivalents as well as proteome and transcriptome analysis patient-derived fibroblasts revealed significant changes of extracellular matrix (ECM)-related genes and proteins. In an exemplary study, the effect of five ECM-related compounds (complement factor C3, fibronectin, syndecan-4 (SD-4), cluster of differentiation 44 (CD44), and thrombospondin-1 (TSP-1)) was tested on bronchial epithelial equivalents and naïve activated CD4+ T cells. For all compounds, an asthma-like inflammation was induced in bronchial epithelial equivalents. Furthermore, a compound-specific polarization of naïve activated CD4+ T cells into different Th subsets was observed. In addition to the human-based in vitro co-culture model, three out of five ECM-related compounds (SD-4, CD44, and TSP-1) were tested in vivo in healthy BALB/c mice in the context of a translational study. In line with the in vitro experiments, a polarization of murine CD4+ T cells towards Th1, Th17, and Th22 subtypes was observed in a first low-dose approach. Interestingly, no histological changes in skin and lung were observed. However, treated mice had an increased size and weight of spleen. Taken together, the established human-based two-organ co-culture system not only enables investigation of the crosstalk between healthy skin and bronchus, but also of the pathophysiological communication in the context of the atopic march by using diseased skin equivalents. The results of this thesis demonstrate the importance of ECM in the complex pathophysiology of the atopic march - a hitherto underestimated feature. In this regard, further research is needed to finally assess new targets for the prevention of the atopic march.