RAS-activated PI3K/AKT signaling sustains cellular senescence in experimental models of psoriasis via P53/P21 axis

Abstract

Abstract Psoriasis is a chronic immune-mediated skin disease in which upper epidermal keratinocytes exhibit a senescent-like phenotype. In psoriatic skin, a variety of inflammatory cytokines can activate intracellular pathways including phosphatidylinositol 3-kinase (PI3K)/AKT signaling and RAS effectors. AKT and RAS participate to cellular senescence, but currently their role in senescence responses occurring in psoriasis have not yet been investigated. Here, we found AKT hyperactivation associated to the upregulation of senescence markers in psoriatic keratinocyte cultures subjected to multiple passages to promote senescence in vitro, as well as in skin lesions of patients affected by psoriasis. AKT-induced senescence was sustained by constitutive RAS activation, and PI3K/AKT pharmacological inhibition contrasted senescence processes induced by cytokines in psoriatic keratinocyte cultures. Additionally, RAS overexpression in the suprabasal epidermis in a murine model of psoriasis was accompanied by AKT upregulation, increase of senescence marker expression and by skin inflammation. In this model, both senescence and inflammation were significantly reduced by selective AKT inhibition. Therefore, targeting RAS-AKT pathway could be a promising novel strategy to counteract multiple psoriasis symptoms.