Research Article: PLA2G2F/lysoplasmalogen axis links epidermal lipid metabolism to type 2 inflammation and itch in atopic dermatitis
Abstract:
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 A 2 (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 PLA 2 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.
Introduction:
Atopic dermatitis is a common, chronic relapsing inflammatory skin disease characterized by dry skin and pruritic eczematous lesions, affecting 10–20% of individuals in developed countries. Histologically, atopic dermatitis is associated with epidermal hyperplasia and the infiltration of inflammatory cells, including lymphocytes, eosinophils, and mast cells. The pathogenesis of atopic dermatitis is driven by the interplay among type 2 immune dysregulation, skin barrier dysfunction, and pruritus, which mutually…
Read more