RESUMEN
Altered epidermal differentiation along with increased keratinocyte proliferation is a characteristic feature of psoriasis and pityriasis rubra pilaris (PRP). However, despite this large degree of overlapping clinical and histologic features, the molecular signatures these skin disorders share are unknown. Using global transcriptomic profiling, we demonstrate that plaque psoriasis and PRP skin lesions have high overlap, with all differentially expressed genes in PRP relative to normal skin having complete overlap with those in psoriasis. The major common pathway shared between psoriasis and PRP involves the phospholipases PLA2G2F, PLA2G4D, and PLA2G4E, which were found to be primarily expressed in the epidermis. Gene silencing each of the 3 PLA2s led to reduction in immune responses and epidermal thickness both in vitro and in vivo in a mouse model of psoriasis, establishing their proinflammatory roles. Lipidomic analyses demonstrated that PLA2s affect mobilization of a phospholipid-eicosanoid pool, which is altered in psoriatic lesions and functions to promote immune responses in keratinocytes. Taken together, our results highlight the important role of PLA2s as regulators of epidermal barrier homeostasis and inflammation, identify PLA2s as a shared pathogenic mechanism between PRP and psoriasis, and as potential therapeutic targets for both diseases.
Asunto(s)
Fosfolipasas A2/metabolismo , Pitiriasis Rubra Pilaris/enzimología , Psoriasis/enzimología , Animales , Humanos , RatonesRESUMEN
Studies with the use of Fe2(+)-induced chemiluminescence of apo-beta-lipoproteins and electron histochemistry have revealed that PUVA therapy and vitamin A high doses enhance lipid peroxidation and activate adenylate cyclase in patients with Devergie's disease. This finding permits a conclusion on the usefulness of enhancing lipid peroxidation in order to reduce cellular mitotic activity.