Extracellular Matrix Remodeling in Atopic Dermatitis Harnesses the Onset of an Asthmatic Phenotype and Is a Potential Contributor to the Atopic March

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 bio-engineered atopic-like skin disease models and three-dimensional bronchial epithelial models trig-gering an asthma-like phenotype in the latter. A subsequent secretome analysis identified thrombos-pondin-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 stud-ied the involvement of the ECM, unveiling distinct proteomic, transcriptomic, and ultrastructural dif-ferences 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 dis-cussed 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.