Oral Presentation Australasian Society for Dermatological Research Annual Scientific Meeting 2017

The mechanosensor YAP drives cutaneous type 2 inflammation and eczema development (#13)

Veronica Mendoza-Reinoso 1 , Susan Corley 2 , Marc Wilkins 2 , Ben Roediger 3 , Annemiek Beverdam 1
  1. School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
  2. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
  3. Skin Inflammation Group, Centenary Institute, Sydney, NSW, Australia

One in five children in the Western world is affected by eczema. This allergic skin disease develops as a result of intrinsic epidermal barrier defects, which drive a local and systemic ‘type 2’ immune response, leading to a pathological cycle of itching, scratching and inflammation, and eventually the potentiation of allergic sensitisation.  The exact mechanism of how epidermal barrier dysfunction, itch and type 2 inflammation connect at the molecular level remains poorly understood.

Yes-associated protein (YAP) is a mechanosensor that responds to mechanical stimuli to control tissue homeostasis. In this project, RNA-Seq analysis identified approximately 1500 differentially expressed genes (FDR = 0.05) in YAP2-5SA-ΔC skin with increased nuclear YAP activity in the basal epidermis. This analysis highlighted genes that encode proteins involved in type 2 immune response, including the cytokine IL-33, a key driver of type 2 inflammation. Furthermore, we found increased RNA levels of the protease Cathepsin S (CTSS), a likely mediator of itch, in YAP2-5SA-ΔC skin, whereas YAP depletion in HaCaT keratinocytes resulted in reduced CTSS protein expression. 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. Lastly, nuclear YAP activity was detected in spongiotic areas of human eczema biopsies, that also express IL33 and CTSS at high levels, underscoring the clinical relevance of our findings.

Together, our studies identify YAP as a hitherto unrecognised upstream inducer of cutaneous atopic inflammation, and provide fundamental insights into the mechanisms of allergic sensitisation in vivo. This has allowed us to define novel targets for therapy and early intervention in atopic individuals and treatment strategies for individuals with established disease.

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