{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T05:34:08Z","timestamp":1789450448519,"version":"build-2803163510"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T00:00:00Z","timestamp":1619049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The amount of mucin secreted by conjunctival goblet cells is regulated to ensure the optimal level for protection of the ocular surface. Under physiological conditions lipid specialized pro-resolving mediators (SPM) are essential for maintaining tissue homeostasis including the conjunctiva. The protein Annexin A1 (AnxA1) can act as an SPM. We used cultured rat conjunctival goblet cells to determine if AnxA1 stimulates an increase in intracellular [Ca<jats:sup>2+<\/jats:sup>] ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) and mucin secretion and to identify the signaling pathways. The increase in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> was determined using fura2\/AM and mucin secretion was measured using an enzyme-linked lectin assay. AnxA1 stimulated an increase in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> and mucin secretion that was blocked by the cell-permeant Ca<jats:sup>2+<\/jats:sup> chelator BAPTA\/AM and the ALX\/FPR2 receptor inhibitor BOC2. AnxA1 increased [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> to a similar extent as the SPMs lipoxin A<jats:sub>4<\/jats:sub> and Resolvin (Rv) D1 and histamine. The AnxA1 increase in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> and mucin secretion were inhibited by blocking the phospholipase C (PLC) pathway including PLC, the IP<jats:sub>3<\/jats:sub> receptor, the Ca<jats:sup>2+<\/jats:sup>\/ATPase that causes the intracellular Ca<jats:sup>2+<\/jats:sup> stores to empty, and blockade of Ca<jats:sup>2+<\/jats:sup> influx. Inhibition of protein kinase C (PKC) and Ca<jats:sup>2+<\/jats:sup>\/calmodulin-dependent protein kinase also decreased the AnxA1-stimulated increase in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> and mucin secretion. In contrast inhibitors of ERK 1\/2, phospholipase A<jats:sub>2<\/jats:sub> (PLA<jats:sub>2<\/jats:sub>), and phospholipase D (PLD) did not alter AnxA1-stimulated increase in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>, but did inhibit mucin secretion. Activation of protein kinase A did not decrease either the AnxA1-stimulated rise in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> or secretion. We conclude that in health, AnxA1 contributes to the mucin layer of the tear film and ocular surface homeostasis by activating the PLC signaling pathway to increase [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> and stimulate mucin secretion and ERK1\/2, PLA<jats:sub>2<\/jats:sub>, and PLD to stimulate mucin secretion from conjunctival goblet cells.<\/jats:p>","DOI":"10.3389\/fimmu.2021.618653","type":"journal-article","created":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T09:28:38Z","timestamp":1619083718000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":26,"title":["Pro-Resolving Mediator Annexin A1 Regulates Intracellular Ca2+ and Mucin Secretion in Cultured Goblet Cells Suggesting a New Use in Inflammatory Conjunctival Diseases"],"prefix":"10.3389","volume":"12","author":[{"given":"Anne V.","family":"Lyngstadaas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus V.","family":"Olsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Bair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin R.","family":"Hodges","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tor P.","family":"Utheim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles N.","family":"Serhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darlene A.","family":"Dartt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2013.7","article-title":"Resolvin D1 and aspirin-triggered resolvin D1 regulate histamine-stimulated conjunctival goblet cell secretion","volume":"6","author":"Li","year":"2013","journal-title":"Mucosal Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20110327","article-title":"Specialized proresolving mediator targets for RvE1 and RvD1 in peripheral blood and mechanisms of resolution","volume":"437","author":"Fredman","year":"2011","journal-title":"Biochem J"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1000833","article-title":"Conjunctival goblet cell secretion stimulated by leukotrienes is reduced by resolvins D1 and E1 to promote resolution of inflammation","volume":"186","author":"Dartt","year":"2011","journal-title":"J Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nri2294","article-title":"Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators","volume":"8","author":"Serhan","year":"2008","journal-title":"Nat Rev Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s11745-004-1339-7","article-title":"Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their endogenous aspirin-triggered epimers","volume":"39","author":"Serhan","year":"2004","journal-title":"Lipids"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/ni1276","article-title":"Resolution of inflammation: the beginning programs the end","volume":"6","author":"Serhan","year":"2005","journal-title":"Nat Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1038\/nri2470","article-title":"Annexin A1 and glucocorticoids as effectors of the resolution of inflammation","volume":"9","author":"Perretti","year":"2009","journal-title":"Nat Rev Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1097\/ACI.0000000000000098","article-title":"Conjunctival epithelial and goblet cell function in chronic inflammation and ocular allergic inflammation","volume":"14","author":"Dartt","year":"2014","journal-title":"Curr Opin Allergy Clin Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2003.10.005","article-title":"Control of mucin production by ocular surface epithelial cells","volume":"78","author":"Dartt","year":"2004","journal-title":"Exp eye Res"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.17-21914","article-title":"Resolvin D1 Increases Mucin Secretion in Cultured Rat Conjunctival Goblet Cells via Multiple Signaling Pathways","volume":"58","author":"Lippestad","year":"2017","journal-title":"Investigative Ophthalmol Vis Sci"},{"key":"B11","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.exer.2018.04.015","article-title":"Signaling pathways activated by resolvin E1 to stimulate mucin secretion and increase intracellular Ca(2+) in cultured rat conjunctival goblet cells","volume":"173","author":"Lippestad","year":"2018","journal-title":"Exp Eye Res"},{"key":"B12","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1038\/mi.2016.33","article-title":"Lipoxin A4 activates ALX\/FPR2 receptor to regulate conjunctival goblet cell secretion","volume":"10","author":"Hodges","year":"2017","journal-title":"Mucosal Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-08-3099","article-title":"Annexin 1 and its bioactive peptide inhibit neutrophil-endothelium interactions under flow: indication of distinct receptor involvement","volume":"107","author":"Hayhoe","year":"2006","journal-title":"Blood"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fimmu.2012.00354","article-title":"Annexin A1 and the regulation of innate and adaptive immunity","volume":"3","author":"Gavins","year":"2012","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1210\/er.21.1.55","article-title":"How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions","volume":"21","author":"Sapolsky","year":"2000","journal-title":"Endocrine Rev"},{"key":"B16","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.prostaglandins.2011.11.005","article-title":"Anti-inflammatory drugs, eicosanoids and the annexin A1\/FPR2 anti-inflammatory system","volume":"98","author":"Yazid","year":"2012","journal-title":"Prostaglandins Other Lipid Mediat"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00938","article-title":"Annexin-A1: Therapeutic Potential in Microvascular Disease","volume":"10","author":"Purvis","year":"2019","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.18-2476","article-title":"Activation of the EGF Receptor by Histamine Receptor Subtypes Stimulates Mucin Secretion in Conjunctival Goblet Cells","volume":"59","author":"He","year":"2018","journal-title":"Invest Ophthalmol Visual Sci"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.12-11264","article-title":"Effect of VIP on intracellular [Ca2+], extracellular regulated kinase 1\/2, and secretion in cultured rat conjunctival goblet cells","volume":"54","author":"Li","year":"2013","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1006\/exer.2000.0915","article-title":"Regulation of conjunctival goblet cell secretion by Ca(2+)and protein kinase C","volume":"71","author":"Dartt","year":"2000","journal-title":"Exp Eye Res"},{"key":"B21","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.exer.2013.07.027","article-title":"Tear Film Mucins: Front Line Defenders of the Ocular Surface; Comparison with Airway and Gastrointestinal Tract Mucins","volume":"117","author":"Hodges","year":"2013","journal-title":"Exp eye Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.12-10163","article-title":"Effect of histamine on Ca(2+)-dependent signaling pathways in rat conjunctival goblet cells","volume":"53","author":"Li","year":"2012","journal-title":"Invest Ophthalmol Visual Sci"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2013\/636812","article-title":"Modulation of Conjunctival Goblet Cell Function by Inflammatory Cytokines","volume":"2013","author":"Contreras-Ruiz","year":"2013","journal-title":"Mediators Inflamm"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2993","DOI":"10.1167\/iovs.11-8748","article-title":"Role of histamine and its receptor subtypes in stimulation of conjunctival goblet cell secretion","volume":"53","author":"Hayashi","year":"2012","journal-title":"Invest Ophthalmol Visual Sci"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M007524200","article-title":"Signaling pathways underlying muscarinic receptor-induced [Ca2+]i oscillations in HEK293 cells","volume":"276","author":"Luo","year":"2001","journal-title":"J Biol Chem"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80323-8","article-title":"A novel ligand of the formyl peptide receptor: annexin I regulates neutrophil extravasation by interacting with the FPR","volume":"5","author":"Walther","year":"2000","journal-title":"Mol Cell"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.advenzreg.2011.09.005","article-title":"Phospholipase C Signaling and Calcium Influx","volume":"52","author":"Putney","year":"2012","journal-title":"Adv Biol Regul"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.29846","article-title":"Maresin 1, a specialized proresolving mediator, stimulates intracellular [Ca(2+)] and secretion in conjunctival goblet cells","volume":"236","author":"Olsen","year":"2021","journal-title":"J Cell Physiol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbior.2014.10.001","article-title":"Role of IP3 receptor signaling in cell functions and diseases","volume":"57","author":"Mikoshiba","year":"2015","journal-title":"Adv Biol Regul"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2016.06.001","article-title":"The Ca(2+)\/Calmodulin\/CaMKK2 Axis: Nature\u2019s Metabolic CaMshaft","volume":"27","author":"Marcelo","year":"2016","journal-title":"Trends Endocrinol metabol: TEM"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00582.2001","article-title":"Cholinergic agonists transactivate EGFR and stimulate MAPK to induce goblet cell secretion","volume":"284","author":"Kanno","year":"2003","journal-title":"Am J Physiol Cell Physiol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1007\/978-1-4615-0717-8_41","article-title":"Role of mitogen-activated protein kinase in cholinergic stimulation of conjunctival goblet cell secretion","volume":"506","author":"Dartt","year":"2002","journal-title":"Adv Exp Med Biol"},{"key":"B33","first-page":"789","article-title":"Phospholipase D in cell proliferation and cancer","volume":"1","author":"Foster","year":"2003","journal-title":"Mol Cancer Research: MCR"},{"key":"B34","article-title":"Pharmacology of Store-Operated Calcium Entry Channels","volume-title":"Calcium Entry Channels in Non-Excitable Cells","author":"Bird","year":"2018"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13109","article-title":"Annexin A1 mimetic peptide controls the inflammatory and fibrotic effects of silica particles in mice","volume":"172","author":"Trentin","year":"2015","journal-title":"Br J Pharmacol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.intimp.2010.10.006","article-title":"Comparative analysis of Annexin A1-formyl peptide receptor 2\/ALX expression in human leukocyte subsets","volume":"11","author":"Spurr","year":"2011","journal-title":"Int Immunopharmacol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1124\/pr.58.3.4","article-title":"The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo","volume":"58","author":"Chiang","year":"2006","journal-title":"Pharmacol Rev"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M513025200","article-title":"Annexin I regulates SKCO-15 cell invasion by signaling through formyl peptide receptors","volume":"281","author":"Babbin","year":"2006","journal-title":"J Biol Chem"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2018.05.028","article-title":"Formyl peptide receptor activation inhibits the expansion of effector T cells and synovial fibroblasts and attenuates joint injury in models of rheumatoid arthritis","volume":"61","author":"Odobasic","year":"2018","journal-title":"Int Immunopharmacol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2018.04.003","article-title":"The G-Protein-Coupled Receptor ALX\/Fpr2 Regulates Adaptive Immune Responses in Mouse Submandibular Glands","volume":"188","author":"Wang","year":"2018","journal-title":"Am J Pathol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"74","DOI":"10.2353\/ajpath.2010.090678","article-title":"Endogenous LXA4 circuits are determinants of pathological angiogenesis in response to chronic injury","volume":"176","author":"Leedom","year":"2010","journal-title":"Am J Pathol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1188","DOI":"10.3390\/cells9051188","article-title":"Annexin A1\/Formyl Peptide Receptor Pathway Controls Uterine Receptivity to the Blastocyst","volume":"9","author":"Hebeda","year":"2020","journal-title":"Cells"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1308253110","article-title":"Ligand-specific conformational change of the G-protein-coupled receptor ALX\/FPR2 determines proresolving functional responses","volume":"110","author":"Cooray","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12665","article-title":"Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7","volume":"171","author":"Back","year":"2014","journal-title":"Br J Pharmacol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2004.04514.x","article-title":"Identification of functional domains in the formyl peptide receptor-like 1 for agonist-induced cell chemotaxis","volume":"272","author":"Le","year":"2005","journal-title":"FEBS J"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1096\/fj.10-159913","article-title":"FPR2\/ALX receptor expression and internalization are critical for lipoxin A4 and annexin-derived peptide-stimulated phagocytosis","volume":"24","author":"Maderna","year":"2010","journal-title":"FASEB J"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1002\/wsbm.1203","article-title":"beta-Arrestin-kinase scaffolds: turn them on or turn them off","volume":"5","author":"Lin","year":"2013","journal-title":"Wiley Interdiscip Rev Syst Biol Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-05-1431","article-title":"Serum amyloid A induces IL-8 secretion through a G protein-coupled receptor, FPRL1\/LXA4R","volume":"101","author":"He","year":"2003","journal-title":"Blood"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3390\/ijms14047193","article-title":"Distinct Signaling Cascades Elicited by Different Formyl Peptide Receptor 2 (FPR2) Agonists","volume":"14","author":"Cattaneo","year":"2013","journal-title":"Int J Mol Sci"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1096\/fj.02-0941fje","article-title":"A novel calcium-dependent proapoptotic effect of annexin 1 on human neutrophils","volume":"17","author":"Solito","year":"2003","journal-title":"FASEB J"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/S0161-5890(02)00074-3","article-title":"Serine\/threonine protein kinases synergistically regulate phospholipase D1 and 2 and secretion in RBL-2H3 mast cells","volume":"38","author":"Chahdi","year":"2002","journal-title":"Mol Immunol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1172\/JCI76693","article-title":"Annexin A1-containing extracellular vesicles and polymeric nanoparticles promote epithelial wound repair","volume":"125","author":"Leoni","year":"2015","journal-title":"J Clin Invest"},{"key":"B53","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1038\/nrrheum.2013.126","article-title":"Annexin A1: potential for glucocorticoid sparing in RA","volume":"9","author":"Yang","year":"2013","journal-title":"Nat Rev Rheumatol"},{"key":"B54","doi-asserted-by":"publisher","first-page":"e0130484","DOI":"10.1371\/journal.pone.0130484","article-title":"Pharmacological Treatment with Annexin A1 Reduces Atherosclerotic Plaque Burden in LDLR-\/- Mice on Western Type Diet","volume":"10","author":"Kusters","year":"2015","journal-title":"PLoS One"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2012.02176.x","article-title":"Reperfusion-induced myocardial dysfunction is prevented by endogenous annexin-A1 and its N-terminal-derived peptide Ac-ANX-A1(2-26)","volume":"168","author":"Qin","year":"2013","journal-title":"Br J Pharmacol"},{"key":"B56","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.pharmthera.2014.11.012","article-title":"Cardioprotective potential of annexin-A1 mimetics in myocardial infarction","volume":"148","author":"Qin","year":"2015","journal-title":"Pharmacol Ther"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1152\/nips.01424.2002","article-title":"Annexin 1: an endogenous anti-inflammatory protein","volume":"18","author":"Perretti","year":"2003","journal-title":"News Physiol Sci: an Int J Physiol Produced Jointly by Int Union Physiol Sci Am Physiol Soc"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00483.x","article-title":"Exploiting the Annexin A1 pathway for the development of novel anti-inflammatory therapeutics","volume":"158","author":"Perretti","year":"2009","journal-title":"Br J Pharmacol"},{"key":"B59","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2016\/8239258","article-title":"Annexin A1 and the Resolution of Inflammation: Modulation of Neutrophil Recruitment, Apoptosis, and Clearance","volume":"2016","author":"Sugimoto","year":"2016","journal-title":"J Immunol Res"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(97)01116-4","article-title":"Endogenous interaction","volume":"18","author":"Perretti","year":"1997","journal-title":"Trends Pharmacol Sci"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.618653\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T09:28:43Z","timestamp":1619083723000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.618653\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,22]]},"references-count":60,"alternative-id":["10.3389\/fimmu.2021.618653"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.618653","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,22]]},"article-number":"618653"}}