The aim of the presented study was to identify regulators and effectors by which the skin orchestrates balanced defense while promoting regenerative responses to maintain skin barrier integrity and function during life. The mTOR (mammalian target of rapamycin) signalling pathway is essential for cell growth and metabolism. Mutations altering mTOR signalling have been implicated in diabetes, cancer as well as skin diseases. Here we unraveled a specific role of mTORC2 signalling in epidermal barrier formation. Epidermal mTORC2 signalling was disrupted by deleting Rictor, encoding an essential subunit of mTORC2 in mouse epidermis (RicEKO). Epidermal structure and barrier function were investigated by a combination of gene expression, biochemical, morphological and functional analysis in RicEKO and control mice. RicEKO newborns displayed an ichthyosis-like phenotype characterized by dysregulated epidermal de novo lipid synthesis, altered lipid lamellae structure, and aberrant filaggrin processing. Impaired epidermal function in RicEKO mice was demonstrated by increased transepidermal water loss, enhanced corneocyte fragility, perturbed immune cell composition, an exaggerated percutaneous immune response, and an enhanced type 2 immune signature in the skin. Restoration of Akt-Ser473 phosphorylation in mTORC2-deficient keratinocytes by expression of constitutive Akt rescued filaggrin processing. Our findings reveal a critical metabolic signalling relay of barrier formation where epidermal mTORC2 activity controls filaggrin processing and de novo epidermal lipid synthesis during cornification. mTORC2-regulated pathways are druggable and could serve as potential novel therapeutic targets to restore barrier function in inflammatory skin diseases.

ESDR106 - Dysfunctional mTORC2 signalling as potential risk factor for inflammatory skin diseases

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING