Group <scp>III</scp> secreted phospholipase <scp>A₂</scp>‐driven lysophospholipid pathway protects against allergic asthma

<jats:title>Abstract</jats:title><jats:p>Asthma is a chronic inflammatory disease of the airways characterized by recurrent episodes of airway obstruction, hyperresponsiveness, remodeling, and eosinophilia. Phospholipase A<jats:sub>2</jats:sub>s (PLA<jats:sub>2</jats:sub>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<jats:sub>2</jats:sub> subtypes and asthma is still incomplete. Here, we show that group III‐secreted PLA<jats:sub>2</jats:sub> (sPLA<jats:sub>2</jats:sub>‐III) plays an ameliorating, rather than aggravating, role in asthma pathology. In both mouse and human lungs, sPLA<jats:sub>2</jats:sub>‐III was expressed in bronchial epithelial cells and decreased during the asthmatic response. In an ovalbumin (OVA)‐induced asthma model, <jats:italic>Pla2g3</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup> mice exhibited enhanced airway hyperresponsiveness, eosinophilia, OVA‐specific IgE production, and type 2 cytokine expression as compared to <jats:italic>Pla2g3</jats:italic><jats:sup><jats:italic>+/+</jats:italic></jats:sup> mice. Lipidomics analysis showed that the pulmonary levels of several lysophospholipids, including lysophosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidic acid (LPA), were decreased in OVA‐challenged <jats:italic>Pla2g3</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup> mice relative to <jats:italic>Pla2g3</jats:italic><jats:sup><jats:italic>+/+</jats:italic></jats:sup> mice. LPA receptor 2 (LPA<jats:sub>2</jats:sub>) agonists suppressed thymic stromal lymphopoietin (TSLP) expression in bronchial epithelial cells and reversed airway hyperresponsiveness and eosinophilia in <jats:italic>Pla2g3</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup> mice, suggesting that sPLA<jats:sub>2</jats:sub>‐III negatively regulates allergen‐induced asthma at least by producing LPA. Thus, the activation of the sPLA<jats:sub>2</jats:sub>‐III‐LPA pathway may be a new therapeutic target for allergic asthma.</jats:p>