Lysophosphatidic Acid Receptor 5 (LPA5) Antagonist AS2717638 Attenuates Allergic Asthma by Reducing Mast Cell Degranulation and Th2 Inflammation in Mice

Lysophosphatidic acid receptor 5 (LPA5, formerly designated GPR92) is a G protein-coupled receptor that recognizes lysophosphatidic acid. Previous studies have indicated that the absence of LPA5 confers protection against the development of neuropathic pain. Although LPA5 expression has been identified in mast cells, macrophages, and microglia, its specific contribution to allergic responses remains insufficiently characterized. In this study, we evaluated the therapeutic potential of LPA5 inhibition in allergic asthma. To this end, the effects of the selective LPA5 antagonist 6,7-dimethoxy-2-(5-methyl-1,2-benzisoxazol-3-yl)-4-(1-piperidinylcarbonyl)-1(2H)-isoquinolinone (AS2717638) were examined using both an in vitro mast cell degranulation model and an in vivo ovalbumin-induced asthma model in BALB/c mice. In RBL-2H3 cells expressing the lpar5 gene, AS2717638 treatment attenuated antigen-induced degranulation. In vivo, administration of AS2717638 reduced airway resistance triggered by ovalbumin exposure. Furthermore, treatment with AS2717638 led to a decrease in eosinophil and lymphocyte infiltration, as well as reduced levels of inflammatory cytokines in bronchoalveolar lavage fluid. Histopathological analysis additionally demonstrated diminished pulmonary inflammation following AS2717638 administration, accompanied by significant reductions in cytokine expression within lung tissue. Collectively, these findings suggest that pharmacological inhibition of LPA5 using AS2717638 mitigates key features of allergic asthma, supporting LPA5 as a potential therapeutic target for this condition.