| Popis: |
The development of atopic dermatitis (AD) in infancy, and subsequent allergic rhinitis, food allergies, and asthma in later childhood, is known as the atopic march. The mechanism is largely unknown, yet the course of disease indicates the contribution of inter-epithelial crosstalk, through to the onset of inflammation in the skin and progression to another mucosal epithelium.Here, we investigated if and how skin-lung epithelial crosstalk could contribute to the development of the atopic march. First, we emulated this inter-epithelial crosstalk through indirect co-culture of bioengineered atopic-like skin disease models and three-dimensional bronchial epithelial models triggering an asthma-like phenotype in the latter. A subsequent secretome analysis identified throm-bospondin-1, CD44, complement factor C3, fibronectin, and syndecan-4 as potentially relevant skin-derived mediators. As these mediators are extracellular matrix (ECM)-related proteins, we then studied the involvement of the ECM, unveiling distinct proteomic, transcriptomic, and ultrastructural differences in atopic samples. The latter indicated ECM remodeling triggering the release of the above-mentioned mediators. In addition to pro-inflammatory effects in lung tissue, the ECM mediators also exert distinct effects on CD4+ T cells. In vivo mouse data showed that exposure to these mediators over seven days dysregulated activated circadian clock genes which have been previously discussed in the context of atopic diseases and asthma development.We hypothesize the existence of a skin-lung axis that could contribute to the atopic march driven by skin ECM remodeling.One Sentence SummaryAtopic skin harbors the progression of atopic diseases to lung tissue through a skin-lung axis that contributes to the atopic march via extracellular matrix remodeling. |
