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 A(2)s (PLA(2)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 PLA(2) subtypes and asthma is still incomplete. Here, we show that group III-secreted PLA(2) (sPLA(2)-III) plays an ameliorating, rather than aggravating, role in asthma pathology. In both mouse and human lungs, sPLA(2)-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 (LPA(2)) agonists suppressed thymic stromal lymphopoietin (TSLP) expression in bronchial epithelial cells and reversed airway hyperresponsiveness and eosinophilia in Pla2g3(-/- )mice, suggesting that sPLA(2)-III negatively regulates allergen-induced asthma at least by producing LPA. Thus, the activation of the sPLA(2)-III-LPA pathway may be a new therapeutic target for allergic asthma.