Keratinocyte signaling in atopic dermatitis: Investigations in organotypic skin models toward clinical application

A multitude of pathophysiological mechanisms contribute to atopic dermatitis (AD), the most common chronic inflammatory skin disease in the Western population. In the booming therapeutic market for AD, most small molecule and antibody-based drugs target the immunological pathology, while drug development programs focusing on epidermal disease-related signaling processes appear scarce. Here, we highlight key evidence that keratinocytes represent major contributors to AD, including disease onset and progression through the physical, immunological and antimicrobial barrier functions of human skin. Examples are provided of pre-clinical skin models recapitulating features of AD in which keratinocyte-specific genetic, immunologic, microbial or environmental signaling cues can be modeled, and potential druggable pathways can be investigated. In the coming years, precise modelling of disease parameters and investigating cause-effect relationships in keratinocytes should be guided by available biological and clinical data from large (combined) patient cohorts. In addition, the rapid innovations in skin engineering methodologies and read-out technologies will aid in the development of higher throughput disease models for precision medicine.