{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:28:28Z","timestamp":1786969708699,"version":"build-2736575974"},"reference-count":38,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T00:00:00Z","timestamp":1786752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"Korean Ministry of Science, ICT, and Future Planning","doi-asserted-by":"publisher","award":["NRF-2023R1A2C202380"],"award-info":[{"award-number":["NRF-2023R1A2C202380"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms27167296","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:01:26Z","timestamp":1786968086000},"page":"7296","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lysophosphatidic Acid Receptor 5 (LPA5) Antagonist AS2717638 Attenuates Allergic Asthma by Reducing Mast Cell Degranulation and Th2 Inflammation in Mice"],"prefix":"10.3390","volume":"27","author":[{"given":"Seung-Won","family":"Jeong","sequence":"first","affiliation":[{"name":"Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8054-8946","authenticated-orcid":false,"given":"Dong-Soon","family":"Im","sequence":"additional","affiliation":[{"name":"Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Institute of Integrated Pharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Moldovan, O., Chereche\u0219-Pan\u021ba, P., Sas, V., Simon, R., and Man, S.C. (2026). Metabolomic Approaches to Lung Function in Pediatric Asthma: A Narrative Review. Children, 13.","DOI":"10.3390\/children13040544"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12737","DOI":"10.1038\/s41598-026-47822-x","article-title":"Distinct long-term effects on lung function and airway remodeling in ovalbumin and house dust mite mouse models of experimental asthma","volume":"16","author":"Markus","year":"2026","journal-title":"Sci. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5835","DOI":"10.1007\/s10787-025-01963-z","article-title":"Targeted biologic therapies and advanced drug delivery approaches in asthma management: A clinical perspective","volume":"33","author":"Khatoon","year":"2025","journal-title":"Inflammopharmacology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"492","DOI":"10.4062\/biomolther.2020.206","article-title":"Suppressive Effect of CYM50358 S1P(4) Antagonist on Mast Cell Degranulation and Allergic Asthma in Mice","volume":"29","author":"Jeon","year":"2021","journal-title":"Biomol. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"114258","DOI":"10.1016\/j.intimp.2025.114258","article-title":"Oleoylethanolamide ameliorates allergic asthma and atopic dermatitis via activation of GPR119","volume":"149","author":"Lee","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"427","DOI":"10.4062\/biomolther.2020.176","article-title":"4-CMTB Ameliorates Ovalbumin-Induced Allergic Asthma through FFA2 Activation in Mice","volume":"29","author":"Lee","year":"2021","journal-title":"Biomol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"111428","DOI":"10.1016\/j.intimp.2023.111428","article-title":"Free fatty acid 3 receptor agonist AR420626 reduces allergic responses in asthma and eczema in mice","volume":"127","author":"Lee","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"116509","DOI":"10.1016\/j.biopha.2024.116509","article-title":"Free fatty acid receptor 4 (FFA4) activation attenuates obese asthma by suppressing adiposity and resolving metaflammation","volume":"174","author":"Son","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1124\/jpet.105.098848","article-title":"Lysophosphatidic acid binds to and activates GPR92, a G protein-coupled receptor highly expressed in gastrointestinal lymphocytes","volume":"318","author":"Kotarsky","year":"2006","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"23589","DOI":"10.1074\/jbc.M603670200","article-title":"GPR92 as a new G12\/13- and Gq-coupled lysophosphatidic acid receptor that increases cAMP, LPA5","volume":"281","author":"Lee","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"411","DOI":"10.4062\/biomolther.2013.080","article-title":"Intercellular lipid mediators and GPCR drug discovery","volume":"21","author":"Im","year":"2013","journal-title":"Biomol. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1111\/j.1365-2222.2006.02626.x","article-title":"Lysophosphatidic acid is detectable in human bronchoalveolar lavage fluids at baseline and increased after segmental allergen challenge","volume":"37","author":"Georas","year":"2007","journal-title":"Clin. Exp. Allergy"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1186\/1465-9921-10-114","article-title":"Role of lysophosphatidic acid receptor LPA2 in the development of allergic airway inflammation in a murine model of asthma","volume":"10","author":"Zhao","year":"2009","journal-title":"Respir. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nm1685","article-title":"The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak","volume":"14","author":"Tager","year":"2008","journal-title":"Nat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"L547","DOI":"10.1152\/ajplung.00058.2011","article-title":"Lysophosphatidic acid receptor 1 modulates lipopolysaccharide-induced inflammation in alveolar epithelial cells and murine lungs","volume":"301","author":"Zhao","year":"2011","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1164\/rccm.202405-0977OC","article-title":"Efficacy and Safety of Admilparant, an LPA(1) Antagonist, in Pulmonary Fibrosis: A Phase 2 Randomized Clinical Trial","volume":"211","author":"Corte","year":"2025","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.2353\/ajpath.2009.080160","article-title":"Lysophosphatidic acid induces alphavbeta6 integrin-mediated TGF-beta activation via the LPA2 receptor and the small G protein G alpha(q)","volume":"174","author":"Xu","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3784","DOI":"10.4049\/jimmunol.1102956","article-title":"Lpa2 is a negative regulator of both dendritic cell activation and murine models of allergic lung inflammation","volume":"188","author":"Emo","year":"2012","journal-title":"J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Lee, Y.J., and Im, D.S. (2022). Efficacy Comparison of LPA(2) Antagonist H2L5186303 and Agonist GRI977143 on Ovalbumin-Induced Allergic Asthma in BALB\/c Mice. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23179745"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"He, Y., Zhou, H., Huang, X., Qu, Y., Wang, Y., Pei, W., Zhang, R., Chen, S., and You, H. (2022). Infiltration of LPAR5(+) macrophages in osteosarcoma tumor microenvironment predicts better outcomes. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.909932"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.neuropharm.2017.08.032","article-title":"Analgesic effects of novel lysophosphatidic acid receptor 5 antagonist AS2717638 in rodents","volume":"126","author":"Murai","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Lundequist, A., and Boyce, J.A. (2011). LPA5 is abundantly expressed by human mast cells and important for lysophosphatidic acid induced MIP-1\u03b2 release. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0018192"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Qu, L., Du, W., Ren, Z., Chen, M., Wu, X., Cao, X., Rao, G., Tong, X., Huang, F., and Sun, Y. (2026). Vasicine Attenuates Allergic Asthma by Suppressing Mast Cell Degranulation and Th2 Inflammation via Modulation of the Fc\u03b5RI\/Lyn + Syk\/MAPK Pathway. Pharmaceuticals, 19.","DOI":"10.3390\/ph19010190"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"418","DOI":"10.3904\/kjim.2025.374","article-title":"Targeting immune dysregulation in chronic spontaneous urticaria: Beyond antihistamines","volume":"41","author":"Ye","year":"2026","journal-title":"Korean J. Intern. Med."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zhang, L., Liu, J., Zheng, J., Jing, W., Zhang, W., Chen, J., Zhang, X., Cheng, X., and Wei, F. (2026). Identification of Natural Compounds Triggering MRGPRX2-Mediated Calcium Flux and Degranulation in RBL-2H3 Cells. Cells, 15.","DOI":"10.3390\/cells15030287"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Plastira, I., Joshi, L., Bernhart, E., Schoene, J., Specker, E., Nazare, M., and Sattler, W. (2019). Small-Molecule Lysophosphatidic Acid Receptor 5 (LPAR5) Antagonists: Versatile Pharmacological Tools to Regulate Inflammatory Signaling in BV-2 Microglia Cells. Front. Cell. Neurosci., 13.","DOI":"10.3389\/fncel.2019.00531"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Joshi, L., Plastira, I., Bernhart, E., Reicher, H., Triebl, A., K\u00f6feler, H.C., and Sattler, W. (2021). Inhibition of Autotaxin and Lysophosphatidic Acid Receptor 5 Attenuates Neuroinflammation in LPS-Activated BV-2 Microglia and a Mouse Endotoxemia Model. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168519"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s11882-026-01281-6","article-title":"Impact of IL-4\/IL-13 Blockade with Dupilumab on the Microbiome in Type 2 Inflammatory Diseases: A Systematic Review","volume":"26","author":"Mari","year":"2026","journal-title":"Curr. Allergy Asthma Rep."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Luo, W., Hu, J., Xu, W., and Dong, J. (2022). Distinct spatial and temporal roles for Th1, Th2, and Th17 cells in asthma. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.974066"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1007\/s00011-009-0054-2","article-title":"Mouse models of asthma: A comparison between C57BL\/6 and BALB\/c strains regarding bronchial responsiveness, inflammation, and cytokine production","volume":"58","author":"Gueders","year":"2009","journal-title":"Inflamm. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jim.2007.07.011","article-title":"Detection and quantitation of eosinophils in the murine respiratory tract by flow cytometry","volume":"327","author":"Stevens","year":"2007","journal-title":"J. Immunol. Methods"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2320","DOI":"10.1016\/j.ajpath.2025.08.012","article-title":"KLF Transcription Factor 5\/Lysophosphatidic Acid Receptor 5 Induced M2 Macrophage Activation and Inflammation by Modulating Phosphorylation of Mitogen-Activated Protein Kinase Kinase Kinase 7 in Pediatric Asthma","volume":"195","author":"Li","year":"2025","journal-title":"Am. J. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17608","DOI":"10.1074\/jbc.M111.330183","article-title":"Targeted deletion of LPA5 identifies novel roles for lysophosphatidic acid signaling in development of neuropathic pain","volume":"287","author":"Lin","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Gaire, B.P., Lee, C.H., Kim, W., Sapkota, A., Lee, D.Y., and Choi, J.W. (2020). Lysophosphatidic Acid Receptor 5 Contributes to Imiquimod-Induced Psoriasis-Like Lesions through NLRP3 Inflammasome Activation in Macrophages. Cells, 9.","DOI":"10.3390\/cells9081753"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1186\/s12974-016-0701-9","article-title":"1-Oleyl-lysophosphatidic acid (LPA) promotes polarization of BV-2 and primary murine microglia towards an M1-like phenotype","volume":"13","author":"Plastira","year":"2016","journal-title":"J. Neuroinflamm."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Joshi, L., Plastira, I., Bernhart, E., Reicher, H., Koshenov, Z., Graier, W.F., Vujic, N., Kratky, D., Rivera, R., and Chun, J. (2022). Lysophosphatidic Acid Receptor 5 (LPA(5)) Knockout Ameliorates the Neuroinflammatory Response In Vivo and Modifies the Inflammatory and Metabolic Landscape of Primary Microglia In Vitro. Cells, 11.","DOI":"10.3390\/cells11071071"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Sapkota, A., Lee, C.H., Park, S.J., and Choi, J.W. (2020). Lysophosphatidic Acid Receptor 5 Plays a Pathogenic Role in Brain Damage after Focal Cerebral Ischemia by Modulating Neuroinflammatory Responses. Cells, 9.","DOI":"10.3390\/cells9061446"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.jphs.2018.01.001","article-title":"LPA5 signaling is involved in multiple sclerosis-mediated neuropathic pain in the cuprizone mouse model","volume":"136","author":"Tsukahara","year":"2018","journal-title":"J. Pharmacol. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7296\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:06:40Z","timestamp":1786968400000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7296"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,15]]},"references-count":38,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27167296"],"URL":"https:\/\/doi.org\/10.3390\/ijms27167296","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,15]]}}}