The mechanosensor YAP drives cutaneous type 2 inflammation and eczema development

Mendoza-Reinoso V1, Corley S2, Lim JY1, Goh LF3, Tong P4, Wilkins M2, Common JE3, Roediger B4 and Beverdam A1,5

  1. School of Medical Sciences, UNSW Sydney, NSW 2052, Australia.
  2. School of Biotechnology and Biomolecular Sciences, UNSW Sydney, NSW 2052, Australia.
  3. Institute of Medical Biology, A(⁎)STAR, 8A Biomedical Grove, Immunos 06-08, Singapore 138648, Singapore.
  4. Skin Inflammation Group, Centenary Institute, The University of Sydney, NSW 2050, Australia.
  5. School of Biomedical Sciences, The University of Queensland, QLD 4072, Australia.

One in five people in the Western world is affected by atopic dermatitis (AD)/eczema. This allergic skin disease develops as result of intrinsic epidermal barrier defects. These drive a local and systemic type 2 immune response, resulting in a pathological cycle of itching, scratching and inflammation, and eventually in AD pathogenesis. 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. Our transcriptomics analyses demonstrated a strong activation of the type 2 immune response in skin of transgenic mice expressing the dominant active YAP2-5SA-ΔC protein the basal epidermis. Re-assessment of the phenotype of YAP2-5SA-ΔC mice indeed demonstrated behavioral, histological, immunological and genetic features of atopic dermatitis. Interestingly, we also found that YAP was activated in an independent AD mouse model and in skin biopsies of human AD patients. Furthermore, we identified that YAP activity in keratinocytes drives IL-33 and CTSS expression in vitro and in the murine skin in vivo. We propose the YAP2-5SA-ΔC transgenic mouse line as a new mouse model for AD development. Furthermore, we revealed that YAP drives type 2 inflammation and itch, eventually leading to AD pathogenesis, through activation of IL33 and CTSS production in the epidermis. Our studies identify YAP as a hitherto unrecognized upstream inducer of cutaneous atopic inflammation. This provides fundamental insights into the mechanisms of allergic sensitization in vivo, thereby defining novel treatment strategies for individuals with established atopic dermatitis.