PLA2G3-Driven Lysophospholipid Pathway Protects Against Allergic Asthma

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RATIONALE: Asthma is a chronic inflammatory disease of the airways, which is characterized by recurrent episodes of airway obstruction, airway hyperresponsiveness to non-specific stimuli, mucus hyperproduction, and airway remodeling. Phospholipase A 2 s (PLA 2 s) are enzymes that generate free fatty acids and lysophospholipids from membrane phospholipids. PLA 2 s were recently reported to be associated with some inflammatory diseases, but the association between PLA 2 s and asthma has not been explored in detail. We examined how group PLA2 (PLA2G3), a mammalian homolog of anaphylactic bee venom PLA 2 , affects the pathophysiology of allergic asthma. METHODS: We analyzed airway inflammation and responses in an ovalbumin (OVA)-induced model of allergic asthma using Pla2g3 -/-and littermate wild-type (Pla2g +/+ ) mice. RESULTS: Pla2g3 -/-mice exhibited enhanced airway eosinophilia, airway hyperresponsiveness, OVA-specific IgE, and chemokine expression after OVA exposures compared to Pla2g +/+ mice. We evaluated the enzymatic action of sPLA2G3 on lung tissue by lipidomics analysis using electrospray ionization mass spectrometry and found that the levels of several lysophospholipids, including LysoPC, LysoPE, and LPA, were decreased in Pla2g3 -/-mice after OVA exposures. LPA agonist reversed the increased eosinophilic inflammation in Pla2g3 -/-mice. The expression of TSLP on bronchial epithelial cells of Pla2g3 -/-mice was significantly increased by OVA challenge compared with Pla2g +/+ mice and stimulation of LPA agonist restored expression of TSLP on bronchial epithelial cells. CONCLUSIONS: These findings indicate that PLA2G3 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness at least through producing LPA. Thus, the PLA2G3-LPA pathway may be a new therapeutic target of allergic asthma.

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