Group III secreted phospholipase A₂ -driven lysophospholipid pathway protects against allergic asthma

Asthma is a chronic inflammatory disease of the airways characterized by recurrent episodes of airway obstruction, hyperresponsiveness, remodeling, and eosinophilia. Phospholipase A₂ s (PLA₂ s), which release fatty acids and lysophospholipids from membrane phospholipids, have been implicated in exacerbating asthma by generating pro-asthmatic lipid mediators, but an understanding of the association between individual PLA₂ subtypes and asthma is still incomplete. Here, we show that group III-secreted PLA₂ (sPLA₂ -III) plays an ameliorating, rather than aggravating, role in asthma pathology. In both mouse and human lungs, sPLA₂ -III was expressed in bronchial epithelial cells and decreased during the asthmatic response. In an ovalbumin (OVA)-induced asthma model, Pla2g3^-/- mice exhibited enhanced airway hyperresponsiveness, eosinophilia, OVA-specific IgE production, and type 2 cytokine expression as compared to Pla2g3^+/+ mice. Lipidomics analysis showed that the pulmonary levels of several lysophospholipids, including lysophosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidic acid (LPA), were decreased in OVA-challenged Pla2g3^-/- mice relative to Pla2g3^+/+ mice. LPA receptor 2 (LPA₂ ) agonists suppressed thymic stromal lymphopoietin (TSLP) expression in bronchial epithelial cells and reversed airway hyperresponsiveness and eosinophilia in Pla2g3^-/- mice, suggesting that sPLA₂ -III negatively regulates allergen-induced asthma at least by producing LPA. Thus, the activation of the sPLA₂ -III-LPA pathway may be a new therapeutic target for allergic asthma.