Atopic dermatitis is a chronic inflammatory skin disease characterized by type 2 immune responses and severe itching; however, the molecular mechanisms linking lipid metabolism to epithelial–immune signaling remain incompletely understood. Herein, we show that group IIF secreted phospholipase A2 (PLA2G2F), which is induced by type 2 cytokines and selectively generates plasmalogen-derived lysophosphatidylethanolamine (lysoplasmalogen; P-LPE) in keratinocytes, contributes to the aggravation of atopic dermatitis and itching. Genetic deletion of Pla2g2f attenuated IL-33 expression in keratinocytes and reduced epidermal hyperplasia, serum IgE levels, type 2 inflammation and scratching behavior, without directly affecting neuronal structure and function, in a mouse model of atopic dermatitis. Topical application of a secreted PLA2 inhibitor or forcible enzymatic degradation of P-LPE suppressed the itch response in wild-type mice, whereas exogenous P-LPE partially restored scratching behavior in Pla2g2f-deficient mice. Importantly, P-LPE levels were significantly elevated in the stratum corneum of patients with atopic dermatitis and positively correlated with disease severity. Collectively, the present study highlights that the PLA2G2F/P-LPE axis, originally identified in psoriasis, is a key regulator that connects epidermal lipid metabolism to IL-33–mediated type 2 inflammation and itching, suggesting that this pathway could be a novel therapeutic target and biomarker of this disease.
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