{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T02:27:02Z","timestamp":1772159222041,"version":"3.50.1"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T00:00:00Z","timestamp":1610064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>EMR2\/ADGRE2 is an adhesion G protein-coupled receptor differentially expressed by human myeloid cells. It modulates diverse cellular functions of innate immune cells and a missense EMR2 variant is directly responsible for vibratory urticaria. Recently, EMR2 was found to activate NLRP3 inflammasome in monocytes <jats:italic>via<\/jats:italic> interaction with FHR1, a regulatory protein of complement Factor H. However, the functional involvement of EMR2 activation and its signaling mechanisms in eliciting NLRP3 inflammasome activation remain elusive. In this study, we show that EMR2-mediated signaling plays a critical role in triggering the activation (2<jats:sup>nd<\/jats:sup>) signal for the NLRP3 inflammasome in both THP-1 monocytic cell line and primary monocytes. Stimulation of EMR2 by its agonistic 2A1 monoclonal antibody elicits a G\u03b1<jats:sub>16<\/jats:sub>-dependent PLC-\u03b2 activation pathway, inducing the activity of downstream Akt, MAPK, NF-\u03baB, and Ca<jats:sup>2+<\/jats:sup> mobilization, eventually leading to K<jats:sup>+<\/jats:sup> efflux. These results identify EMR2 and its associated signaling intermediates as potential intervention targets of NLRP3 inflammasome activation in inflammatory disorders.<\/jats:p>","DOI":"10.3389\/fimmu.2020.602016","type":"journal-article","created":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T17:41:03Z","timestamp":1610127663000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Stimulation of Vibratory Urticaria-Associated Adhesion-GPCR, EMR2\/ADGRE2, Triggers the NLRP3 Inflammasome Activation Signal in Human Monocytes"],"prefix":"10.3389","volume":"11","author":[{"given":"Kuan-Yu","family":"I","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Yi","family":"Tseng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Chih","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siamon","family":"Gordon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kwai-Fong","family":"Ng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsi-Hsien","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.04.007","article-title":"Mechanisms and functions of inflammasomes","volume":"157","author":"Lamkanfi","year":"2014","journal-title":"Cell"},{"key":"B2","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1111\/imr.12296","article-title":"Regulation of inflammasome activation","volume":"265","author":"Man","year":"2015","journal-title":"Immunol Rev"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cellbio-101011-155745","article-title":"Inflammasomes and their roles in health and disease","volume":"28","author":"Lamkanfi","year":"2012","journal-title":"Annu Rev Cell Dev Biol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nature10759","article-title":"Inflammasomes in health and disease","volume":"481","author":"Strowig","year":"2012","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-031210-101405","article-title":"The inflammasome NLRs in immunity, inflammation, and associated diseases","volume":"29","author":"Davis","year":"2011","journal-title":"Annu Rev Immunol"},{"key":"B6","doi-asserted-by":"publisher","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":"B7","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.207365","article-title":"Inflammasome activation and assembly at a glance","volume":"130","author":"Malik","year":"2017","journal-title":"J Cell Sci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20133328","article-title":"The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation","volume":"20","author":"Kelley","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B9","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1038\/s41419-019-1413-8","article-title":"Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors","volume":"10","author":"Yang","year":"2019","journal-title":"Cell Death Disease"},{"key":"B10","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1016\/j.tips.2018.07.002","article-title":"GPCRs in NLRP3 Inflammasome Activation, Regulation, and Therapeutics","volume":"39","author":"Tang","year":"2018","journal-title":"Trends Pharmacol Sci"},{"key":"B11","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1006\/geno.2000.6238","article-title":"Human EMR2, a novel EGF-TM7 molecule on chromosome 19p13.1, is closely related to CD97","volume":"67","author":"Lin","year":"2000","journal-title":"Genomics"},{"key":"B12","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.tibs.2008.07.005","article-title":"Adhesion-GPCRs: emerging roles for novel receptors","volume":"33","author":"Yona","year":"2008","journal-title":"Trends Biochem Sci"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201141715","article-title":"F4\/80 and the related adhesion-GPCRs","volume":"41","author":"Gordon","year":"2011","journal-title":"Eur J Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1124\/pr.114.009647","article-title":"International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors","volume":"67","author":"Hamann","year":"2015","journal-title":"Pharmacol Rev"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.11.148","article-title":"CD312, the human adhesion-GPCR EMR2, is differentially expressed during differentiation, maturation, and activation of myeloid cells","volume":"353","author":"Chang","year":"2007","journal-title":"Biochem Biophys Res Communications"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1111\/cei.12679","article-title":"Expression of CD11c and EMR2 on neutrophils: potential diagnostic biomarkers for sepsis and systemic inflammation","volume":"182","author":"Lewis","year":"2015","journal-title":"Clin Exp Immunol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"38250","DOI":"10.1038\/srep38250","article-title":"Increased EMR2 expression on neutrophils correlates with disease severity and predicts overall mortality in cirrhotic patients","volume":"6","author":"Huang","year":"2016","journal-title":"Sci Rep"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1096\/fj.07-9435com","article-title":"Ligation of the adhesion-GPCR EMR2 regulates human neutrophil function","volume":"22","author":"Yona","year":"2008","journal-title":"FASEB J Off Publ Fed Am Societies Exp Biol"},{"key":"B19","article-title":"EMR2 receptor ligation modulates cytokine secretion profiles and cell survival of lipopolysaccharide-treated neutrophils","volume":"34","author":"Chen","year":"2011","journal-title":"Chang Gung Med J"},{"key":"B20","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/bs.ai.2017.05.005","article-title":"Adhesion GPCRs in Regulating Immune Responses and Inflammation","volume":"136","author":"Lin","year":"2017","journal-title":"Adv Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1500611","article-title":"Vibratory Urticaria Associated with a Missense Variant in ADGRE2","volume":"374","author":"Boyden","year":"2016","journal-title":"New Engl J Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-11-3540","article-title":"The epidermal growth factor-like domains of the human EMR2 receptor mediate cell attachment through chondroitin sulfate glycosaminoglycans","volume":"102","author":"Stacey","year":"2003","journal-title":"Blood"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/art.20788","article-title":"Identification of the epidermal growth factor-TM7 receptor EMR2 and its ligand dermatan sulfate in rheumatoid synovial tissue","volume":"52","author":"Kop","year":"2005","journal-title":"Arthritis Rheum"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00373","article-title":"Activation of Adhesion GPCR EMR2\/ADGRE2 Induces Macrophage Differentiation and Inflammatory Responses via Galpha16\/Akt\/MAPK\/NF-kappaB Signaling Pathways","volume":"8","author":"I","year":"2017","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2961","DOI":"10.1038\/s41467-019-10766-0","article-title":"Serum FHR1 binding to necrotic-type cells activates monocytic inflammasome and marks necrotic sites in vasculopathies","volume":"10","author":"Irmscher","year":"2019","journal-title":"Nat Communications"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4402194","article-title":"The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation","volume":"14","author":"Fernandes-Alnemri","year":"2007","journal-title":"Cell Death Differ"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-013-3905-0","article-title":"The NLRP3 inflammasome activation in human or mouse cells, sensitivity causes puzzle","volume":"4","author":"Wang","year":"2013","journal-title":"Protein Cell"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-03-146720","article-title":"Differential requirement for the activation of the inflammasome for processing and release of IL-1beta in monocytes and macrophages","volume":"113","author":"Netea","year":"2009","journal-title":"Blood"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0709684105","article-title":"ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1beta and IL-18 secretion in an autocrine way","volume":"105","author":"Piccini","year":"2008","journal-title":"Proc Natl Acad Sci U States A"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.01.012","article-title":"Human Monocytes Engage an Alternative Inflammasome Pathway","volume":"44","author":"Gaidt","year":"2016","journal-title":"Immunity"},{"key":"B31","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1159\/000186689","article-title":"Functions and regulatory mechanisms of Gq-signaling pathways","volume":"17","author":"Mizuno","year":"2009","journal-title":"Neuro Signals"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110390200","article-title":"G Protein beta gamma subunits act on the catalytic domain to stimulate Bruton\u2019s agammaglobulinemia tyrosine kinase","volume":"277","author":"Lowry","year":"2002","journal-title":"J Biol Chem"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-41523-9_15","article-title":"Adhesion GPCRs as Modulators of Immune Cell Function","volume":"234","author":"Hamann","year":"2016","journal-title":"Handb Exp Pharmacol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.71.5.854","article-title":"The human EGF-TM7 family member EMR2 is a heterodimeric receptor expressed on myeloid cells","volume":"71","author":"Kwakkenbos","year":"2002","journal-title":"J Leukocyte Biol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(03)00695-1","article-title":"Proteolytic cleavage of the EMR2 receptor requires both the extracellular stalk and the GPS motif","volume":"547","author":"Chang","year":"2003","journal-title":"FEBS Lett"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.11.036","article-title":"A tethered agonist within the ectodomain activates the adhesion G protein-coupled receptors GPR126 and GPR133","volume":"9","author":"Liebscher","year":"2014","journal-title":"Cell Rep"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1421785112","article-title":"Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist","volume":"112","author":"Stoveken","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2020.03.936","article-title":"Critical Signaling Events in the Mechanoactivation of Human Mast Cells through p.C492Y-ADGRE2","volume":"140","author":"Naranjo","year":"2020","journal-title":"J Invest Dermatol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2013.00470","article-title":"Heparan sulfate: a ubiquitous glycosaminoglycan with multiple roles in immunity","volume":"4","author":"Simon Davis","year":"2013","journal-title":"Front Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.14632","article-title":"The role of innate immunity in mucopolysaccharide diseases","volume":"148","author":"Parker","year":"2019","journal-title":"J Neurochem"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.014266","article-title":"Biglycan, a danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors","volume":"284","author":"Babelova","year":"2009","journal-title":"J Biol Chem"},{"key":"B42","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1186\/1471-2474-15-318","article-title":"Monosodium urate crystal induced macrophage inflammation is attenuated by chondroitin sulphate: pre-clinical model for gout prophylaxis","volume":"15","author":"Orlowsky","year":"2014","journal-title":"BMC Musculoskeletal Disord"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1038\/s41598-020-57989-6","article-title":"G Protein-Coupling of Adhesion GPCRs ADGRE2\/EMR2 and ADGRE5\/CD97, and Activation of G Protein Signalling by an Anti-EMR2 Antibody","volume":"10","author":"Bhudia","year":"2020","journal-title":"Sci Rep"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.602016\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,14]],"date-time":"2021-01-14T04:07:39Z","timestamp":1610597259000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.602016\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,8]]},"references-count":43,"alternative-id":["10.3389\/fimmu.2020.602016"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2020.602016","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,8]]},"article-number":"602016"}}