Transcriptome analysis of hyperplastic skin of TAP2-5SA-ΔC mice identifies molecular mechanisms associated with eczema

V Mendoza-Reinoso1, S Corley2, M Wilkins2, B Roediger3 and A Beverdam1

  1. School of Medical Sciences, UNSW Australia, Sydney, NSW 2052, Australia
  2. School of Biotechnology and Biomolecular Sciences, UNSW Australia, NSW 2052, Australia
  3. Skin Inflammation Group, Centenary Institute, Sydney, NSW 2050

Atopic eczema affects 20% of children in the Western world, and the development of this disease in early life markedly increases the risk of developing asthma and allergic reactions later in childhood. Eczema occurs as a result of intrinsic epidermal barrier defects, which disrupts skin homeostasis and drives a local and systemic ‘type 2’ immune response. The exact mechanism of how this occurs remains poorly understood, although genetic and histologic studies have implicated the epidermal cytokine IL33. Yes-associated protein (YAP) is a mechanosensor that responds to mechanical stimuli to control tissue homeostasis. In this project, transcriptomics analysis identified approximately 2000 differentially expressed genes in YAP2-5SA-ΔC skin with increased nuclear YAP activity in the basal epidermis. Interestingly, a large number of these genes encode proteins involved in type 2 immune response, including IL33. Further investigation revealed that YAP2-5SA-ΔC mice demonstrate behavioural, histological and immunological hallmarks of eczema, establishing this transgenic mouse line as a new animal model for eczema. Furthermore, YAP activity was detected in spongiotic areas of human eczema biopsies, underscoring the clinical relevance of our finding. Interestingly, spongiotic areas of human eczema skin displayed increased expression of both YAP and IL33. Moreover, a highly conserved TEAD binding motif was detected in the Il33 allele of at least 8 vertebrate species. This suggests that YAP may directly activate IL33 production in the aetiology of eczema. Together, this data establishes a role for mechanosensor YAP in eczema development through activation of IL33 production, possibly in response to skin barrier defects and mechanical stimuli such as scratching. The outcomes of this project have health implications for eczema and atopic disease, and other skin diseases displaying activated YAP.