{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T18:32:17Z","timestamp":1770489137767,"version":"3.49.0"},"reference-count":56,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2020,11,14]],"date-time":"2020-11-14T00:00:00Z","timestamp":1605312000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2020R1F1A1067154"],"award-info":[{"award-number":["NRF-2020R1F1A1067154"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2020R1A6A1A03043708"],"award-info":[{"award-number":["NRF-2020R1A6A1A03043708"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lysophosphatidic acid receptor 1 (LPA1) contributes to brain injury following transient focal cerebral ischemia. However, the mechanism remains unclear. Here, we investigated whether nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation might be an underlying mechanism involved in the pathogenesis of brain injury associated with LPA1 following ischemic challenge with transient middle cerebral artery occlusion (tMCAO). Suppressing LPA1 activity by its antagonist attenuated NLRP3 upregulation in the penumbra and ischemic core regions, particularly in ionized calcium-binding adapter molecule 1 (Iba1)-expressing cells like macrophages of mouse after tMCAO challenge. It also suppressed NLRP3 inflammasome activation, such as caspase-1 activation, interleukin 1\u03b2 (IL-1\u03b2) maturation, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) speck formation, in a post-ischemic brain. The role of LPA1 in NLRP3 inflammasome activation was confirmed in vitro using lipopolysaccharide-primed bone marrow-derived macrophages, followed by LPA exposure. Suppressing LPA1 activity by either pharmacological antagonism or genetic knockdown attenuated NLRP3 upregulation, caspase-1 activation, IL-1\u03b2 maturation, and IL-1\u03b2 secretion in these cells. Furthermore, nuclear factor-\u03baB (NF-\u03baB), extracellular signal-regulated kinase 1\/2 (ERK1\/2), and p38 were found to be LPA1-dependent effector pathways in these cells. Collectively, results of the current study first demonstrate that LPA1 could contribute to ischemic brain injury by activating NLRP3 inflammasome with underlying effector mechanisms.<\/jats:p>","DOI":"10.3390\/ijms21228595","type":"journal-article","created":{"date-parts":[[2020,11,16]],"date-time":"2020-11-16T21:48:52Z","timestamp":1605563332000},"page":"8595","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["NLRP3 Inflammasome Activation Is Involved in LPA1-Mediated Brain Injury after Transient Focal Cerebral Ischemia"],"prefix":"10.3390","volume":"21","author":[{"given":"Chi-Ho","family":"Lee","sequence":"first","affiliation":[{"name":"Laboratory of Neuropharmacology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arjun","family":"Sapkota","sequence":"additional","affiliation":[{"name":"Laboratory of Neuropharmacology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bhakta Prasad","family":"Gaire","sequence":"additional","affiliation":[{"name":"Laboratory of Neuropharmacology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji Woong","family":"Choi","sequence":"additional","affiliation":[{"name":"Laboratory of Neuropharmacology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.bbalip.2012.07.015","article-title":"Lysophospholipids and their receptors in the central nervous system","volume":"1831","author":"Choi","year":"2013","journal-title":"Biochim. et Biophys. Acta"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1194\/jlr.R046458","article-title":"LPA receptor signaling: Pharmacology, physiology, and pathophysiology","volume":"55","author":"Yung","year":"2014","journal-title":"J. Lipid Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4062\/biomolther.2014.109","article-title":"Promising Pharmacological Directions in the World of Lysophosphatidic Acid Signaling","volume":"23","author":"Stoddard","year":"2015","journal-title":"Biomol. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12974-019-1555-8","article-title":"Lysophosphatidic acid receptor 1 (LPA1) plays critical roles in microglial activation and brain damage after transient focal cerebral ischemia","volume":"16","author":"Gaire","year":"2019","journal-title":"J. Neuroinflammation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"100020","DOI":"10.1016\/j.ynpai.2018.07.001","article-title":"Lysophosphatidic acid LPA1 and LPA3 receptors play roles in the maintenance of late tissue plasminogen activator-induced central poststroke pain in mice","volume":"5","author":"Ueda","year":"2019","journal-title":"Neurobiol. Pain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.neuroscience.2013.01.005","article-title":"Involvement of LPA1 receptor signaling in cerebral ischemia-induced neuropathic pain","volume":"235","author":"Halder","year":"2013","journal-title":"Neuroscience"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.immuni.2013.08.037","article-title":"Mechanisms of NOD-like Receptor-Associated Inflammasome Activation","volume":"39","author":"Wen","year":"2013","journal-title":"Immunity"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1146\/annurev.immunol.021908.132715","article-title":"The Inflammasomes: Guardians of the Body","volume":"27","author":"Martinon","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"ref_9","first-page":"1","article-title":"Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors","volume":"10","author":"Yang","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/ni.2228","article-title":"A role for the NLRP3 inflammasome in metabolic diseases\u2014did Warburg miss inflammation?","volume":"13","author":"Wen","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.ajpath.2013.09.007","article-title":"New Insights into Mechanisms Controlling the NLRP3 Inflammasome and Its Role in Lung Disease","volume":"184","author":"Latz","year":"2014","journal-title":"Am. J. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.jhep.2012.03.035","article-title":"Inflammasomes in liver diseases","volume":"57","author":"Szabo","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1681\/ASN.2010080798","article-title":"The Inflammasomes in Kidney Disease","volume":"22","author":"Anders","year":"2011","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.cmet.2013.09.010","article-title":"Canonical Nlrp3 Inflammasome Links Systemic Low-Grade Inflammation to Functional Decline in Aging","volume":"18","author":"Youm","year":"2013","journal-title":"Cell Metab."},{"key":"ref_15","first-page":"534","article-title":"Inhibition of the Inflammasome Complex Reduces the Inflammatory Response after Thromboembolic Stroke in Mice","volume":"29","author":"Abulafia","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"154","DOI":"10.3389\/fncel.2017.00154","article-title":"NOSH-NBP, a Novel Nitric Oxide and Hydrogen Sulfide- Releasing Hybrid, Attenuates Ischemic Stroke-Induced Neuroinflammatory Injury by Modulating Microglia Polarization","volume":"11","author":"Ji","year":"2017","journal-title":"Front. Cell. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.expneurol.2017.03.002","article-title":"Purinergic 2X7 receptor\/NLRP3 pathway triggers neuronal apoptosis after ischemic stroke in the mouse","volume":"292","author":"Ye","year":"2017","journal-title":"Exp. Neurol."},{"key":"ref_18","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_19","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1179\/174313208X300369","article-title":"Influence of acetylsalicylate on plasma lysophosphatidic acid level in patients with ischemic cerebral vascular diseases","volume":"30","author":"Li","year":"2008","journal-title":"Neurol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.expneurol.2018.04.010","article-title":"Lysophosphatidic acid induces neuronal cell death via activation of asparagine endopeptidase in cerebral ischemia-reperfusion injury","volume":"306","author":"Wang","year":"2018","journal-title":"Exp. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.tibs.2016.09.002","article-title":"Mechanism and Regulation of NLRP3 Inflammasome Activation","volume":"41","author":"He","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1016\/j.imbio.2012.07.020","article-title":"Acute lipopolysaccharide priming boosts inflammasome activation independently of inflammasome sensor induction","volume":"217","author":"Schroder","year":"2012","journal-title":"Immunobiololgy"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"36617","DOI":"10.1074\/jbc.M112.407130","article-title":"Non-transcriptional Priming and Deubiquitination Regulate NLRP3 Inflammasome Activation","volume":"287","author":"Juliana","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1161\/01.STR.32.5.1208","article-title":"Enhanced Expression of Iba1, Ionized Calcium-Binding Adapter Molecule 1, After Transient Focal Cerebral Ischemia in Rat Brain","volume":"32","author":"Ito","year":"2001","journal-title":"Stroke"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1369\/jhc.6A7156.2007","article-title":"Actin-binding Proteins Coronin-1a and IBA-1 are Effective Microglial Markers for Immunohistochemistry","volume":"55","author":"Ahmed","year":"2007","journal-title":"J. Histochem. Cytochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.immuni.2014.12.031","article-title":"A20 restricts ubiquitination of pro-interleukin-1beta protein complexes and suppresses NLRP3 inflammasome activity","volume":"42","author":"Duong","year":"2015","journal-title":"Immunity"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1007\/s00011-016-0973-7","article-title":"CORM-2 inhibits TXNIP\/NLRP3 inflammasome pathway in LPS-induced acute lung injury","volume":"65","author":"Jiang","year":"2016","journal-title":"Inflamm. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1007\/s12026-017-8901-7","article-title":"NLRP3 inflammasome activation regulated by NF-\u03baB and DAPK contributed to paraquat-induced acute kidney injury","volume":"65","author":"Liu","year":"2017","journal-title":"Immunol. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.3389\/fimmu.2018.02248","article-title":"Inflammatory Potential of Four Different Phases of Calcium Pyrophosphate Relies on NF-kappaB Activation and MAPK Pathways","volume":"9","author":"Renaudin","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_30","first-page":"4399","article-title":"Regulation of the NLRP3 inflammasome and macrophage pyroptosis by the p38 MAPK signaling pathway in a mouse model of acute lung injury","volume":"18","author":"Li","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12515","DOI":"10.1096\/fj.201802805RR","article-title":"Activation of ROS\/MAPKs\/NF-kappaB\/NLRP3 and inhibition of efferocytosis in osteoclast-mediated diabetic osteoporosis","volume":"33","author":"An","year":"2019","journal-title":"FASEB J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"16","DOI":"10.3389\/fnmol.2020.00016","article-title":"Lysophosphatidic Acid Induces Apoptosis of PC12 Cells Through LPA1 Receptor\/LPA2 Receptor\/MAPK Signaling Pathway","volume":"13","author":"Zhang","year":"2020","journal-title":"Front. Mol. Neurosci."},{"key":"ref_33","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_34","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/j.chest.2018.08.1058","article-title":"Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial of BMS-986020, a Lysophosphatidic Acid Receptor Antagonist for the Treatment of Idiopathic Pulmonary Fibrosis","volume":"154","author":"Palmer","year":"2018","journal-title":"Chest"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.lfs.2018.12.040","article-title":"The role of lysophosphatidic acid in the physiology and pathology of the skin","volume":"220","author":"Lei","year":"2019","journal-title":"Life Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.yexcr.2014.11.020","article-title":"Lysophospholipid receptors in drug discovery","volume":"333","author":"Kihara","year":"2015","journal-title":"Exp. Cell Res."},{"key":"ref_37","first-page":"660","article-title":"NLRP3 Deficiency Ameliorates Neurovascular Damage in Experimental Ischemic Stroke","volume":"34","author":"Yang","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-018-24350-x","article-title":"Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke","volume":"8","author":"Ismael","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1159\/000495291","article-title":"Psoriasis: Keratinocytes or Immune Cells\u2014Which Is the Trigger?","volume":"235","author":"Benhadou","year":"2018","journal-title":"Dermatology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1006\/excr.1995.1007","article-title":"Lysophosphatidic Acid Induction of Transforming Growth Factors \u03b1 and \u03b2: Modulation of Proliferation and Differentiation in Cultured Human Keratinocytes and Mouse Skin","volume":"216","author":"Piazza","year":"1995","journal-title":"Exp. Cell Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.3389\/fimmu.2018.01390","article-title":"T Cell Hierarchy in the Pathogenesis of Psoriasis and Associated Cardiovascular Comorbidities","volume":"9","author":"Casciano","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Chi, O.Z., Mellender, S.J., Kiss, G.K., Chiricolo, A., Liu, X., Patel, N., Jacinto, E., and Weiss, H.R. (2020). Lysophosphatidic acid increased infarct size in the early stage of cerebral ischemia-reperfusion with increased BBB permeability. J. Stroke Cerebrovasc. Dis., 29.","DOI":"10.1016\/j.jstrokecerebrovasdis.2020.105029"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1189\/jlb.1109766","article-title":"Inflammatory mechanisms in ischemic stroke: Role of inflammatory cells","volume":"87","author":"Jin","year":"2010","journal-title":"J. Leukoc. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Levard, D., Buendia, I., Lanquetin, A., Glavan, M., Vivien, D., and Rubio, M. (2020). Filling the gaps on stroke research: Focus on inflammation and immunity. Brain Behav. Immun.","DOI":"10.1016\/j.bbi.2020.09.025"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1517\/13543784.9.10.2281","article-title":"Therapeutic potential of anti-inflammatory drugs in focal stroke","volume":"9","author":"Barone","year":"2000","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.2174\/156802609789869619","article-title":"Inflammation as a Therapeutic Target in Acute Ischemic Stroke Treatment","volume":"9","author":"Tuttolomondo","year":"2009","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12974-019-1516-2","article-title":"Neuroinflammation: Friend and foe for ischemic stroke","volume":"16","author":"Jayaraj","year":"2019","journal-title":"J. Neuroinflammation"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"8071","DOI":"10.1007\/s12035-016-0297-1","article-title":"Inflammatory Response in the CNS: Friend or Foe?","volume":"54","author":"Sochocka","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_49","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_50","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/S0028-3908(99)00262-2","article-title":"Functional assessments in mice and rats after focal stroke","volume":"39","author":"Hunter","year":"2000","journal-title":"Neuropharmacology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/S0006-8993(02)03753-8","article-title":"The selective A2A receptor antagonist SCH 58261 reduces striatal transmitter outflow, turning behavior and ischemic brain damage induced by permanent focal ischemia in the rat","volume":"959","author":"Melani","year":"2003","journal-title":"Brain Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"10224","DOI":"10.1523\/JNEUROSCI.4703-14.2015","article-title":"Activation of Lysophosphatidic Acid Receptor Type 1 Contributes to Pathophysiology of Spinal Cord Injury","volume":"35","author":"Lago","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1096\/fj.12-219378","article-title":"LPA 1 -induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation","volume":"27","author":"Sakai","year":"2013","journal-title":"FASEB J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1002\/art.30262","article-title":"Amelioration of dermal fibrosis by genetic deletion or pharmacologic antagonism of lysophosphatidic acid receptor 1 in a mouse model of scleroderma","volume":"63","author":"Castelino","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2682","DOI":"10.1161\/hs1101.098367","article-title":"Intravenous Administration of Human Umbilical Cord Blood Reduces Behavioral Deficits After Stroke in Rats","volume":"32","author":"Chen","year":"2001","journal-title":"Stroke"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1369\/0022155411416007","article-title":"Generation of Mature Murine Monocytes from Heterogeneous Bone Marrow and Description of Their Properties","volume":"59","author":"Francke","year":"2011","journal-title":"J. Histochem. Cytochem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/22\/8595\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:33:26Z","timestamp":1760178806000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/22\/8595"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,14]]},"references-count":56,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["ijms21228595"],"URL":"https:\/\/doi.org\/10.3390\/ijms21228595","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,14]]}}}