Psoriasis is an inflammatory disorder characterized by keratinocyte hyper-proliferation and Th17-type immune responses. However, the roles of bioactive
lipids and the regulation of their biosynthesis in this chronic
skin disease are not fully understood. Herein, we show that group IVE cytosolic
phospholipase A2 (cPLA2 ε/PLA2G4E) plays a counterregulatory role against psoriatic
inflammation by producing the anti-inflammatory
lipid N-acylethanolamine (NAE). Lipidomics analysis of mouse skin revealed that NAE species and their precursors (N-acyl-
phosphatidylethanolamine and glycerophospho-
N-acylethanolamine) were robustly increased in parallel with the ongoing process of
imiquimod (IMQ)-induced
psoriasis, accompanied by a marked upregulation of cPLA2 ε in epidermal keratinocytes. Genetic deletion of cPLA2 ε exacerbated IMQ-induced ear swelling and psoriatic marker expression, with a dramatic reduction of NAE-related
lipids in IMQ-treated, and even normal, skin. Stimulation of cultured human keratinocytes with psoriatic
cytokines concomitantly increased PLA2G4E expression and NAE production, and supplementation with NAEs significantly attenuated the
cytokine-induced upregulation of the psoriatic marker S100A9. Increased expression of cPLA2 ε was also evident in the epidermis of psoriatic patients. These findings reveal for the first time the in vivo role of cPLA2 ε, which is highly induced in the keratinocytes of the psoriatic skin, promotes the biosynthesis of NAE-related
lipids, and contributes to limiting psoriatic
inflammation.