{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T13:19:31Z","timestamp":1780060771850,"version":"3.54.0"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2023,5,30]],"date-time":"2023-05-30T00:00:00Z","timestamp":1685404800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["CRSII3_160719 \/ 1"],"award-info":[{"award-number":["CRSII3_160719 \/ 1"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003006","name":"ETH Zurich","doi-asserted-by":"crossref","award":["Core funding"],"award-info":[{"award-number":["Core funding"]}],"id":[{"id":"10.13039\/501100003006","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["CRSII3_160719 \/ 1"],"award-info":[{"award-number":["CRSII3_160719 \/ 1"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["CRSII3_160719 \/ 1"],"award-info":[{"award-number":["CRSII3_160719 \/ 1"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Atypical chemokine receptor 3 (ACKR3) is a scavenger of the chemokines CXCL11 and CXCL12 and of several opioid peptides. Additional evidence indicates that ACKR3 binds two other non-chemokine ligands, namely the peptide hormone adrenomedullin (AM) and derivatives of the proadrenomedullin N-terminal 20 peptide (PAMP). AM exhibits multiple functions in the cardiovascular system and is essential for embryonic lymphangiogenesis in mice. Interestingly, AM-overexpressing and ACKR3-deficient mouse embryos both display lymphatic hyperplasia. Moreover, <jats:italic>in vitro<\/jats:italic> evidence suggested that lymphatic endothelial cells (LECs), which express ACKR3, scavenge AM and thereby reduce AM-induced lymphangiogenic responses. Together, these observations have led to the conclusion that ACKR3-mediated AM scavenging by LECs serves to prevent overshooting AM-induced lymphangiogenesis and lymphatic hyperplasia. Here, we further investigated AM scavenging by ACKR3 in HEK293 cells and in human primary dermal LECs obtained from three different sources <jats:italic>in vitro<\/jats:italic>. LECs efficiently bound and scavenged fluorescent CXCL12 or a CXCL11\/12 chimeric chemokine in an ACKR3-dependent manner. Conversely, addition of AM induced LEC proliferation but AM internalization was found to be independent of ACKR3. Similarly, ectopic expression of ACKR3 in HEK293 cells did not result in AM internalization, but the latter was avidly induced upon co-transfecting HEK293 cells with the canonical AM receptors, consisting of calcitonin receptor-like receptor (CALCRL) and receptor activity-modifying protein (RAMP)2 or RAMP3. Together, these findings indicate that ACKR3-dependent scavenging of AM by human LECs does not occur at ligand concentrations sufficient to trigger AM-induced responses mediated by canonical AM receptors.<\/jats:p>","DOI":"10.1371\/journal.pone.0285597","type":"journal-article","created":{"date-parts":[[2023,5,30]],"date-time":"2023-05-30T17:28:02Z","timestamp":1685467682000},"page":"e0285597","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Reassessing the adrenomedullin scavenging function of ACKR3 in lymphatic endothelial cells"],"prefix":"10.1371","volume":"18","author":[{"given":"Elena C.","family":"Sigmund","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara D.","family":"Jakobs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hazal","family":"Tatliadim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6431-7555","authenticated-orcid":true,"given":"Carlotta","family":"Tacconi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Thelen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel F.","family":"Legler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0997-1861","authenticated-orcid":true,"given":"Cornelia","family":"Halin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,5,30]]},"reference":[{"issue":"42","key":"pone.0285597.ref001","doi-asserted-by":"crossref","first-page":"35760","DOI":"10.1074\/jbc.M508234200","article-title":"The chemokine SDF-1\/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes","volume":"280","author":"K Balabanian","year":"2005","journal-title":"Journal of Biological Chemistry"},{"issue":"3","key":"pone.0285597.ref002","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1006\/bbrc.1995.2847","article-title":"Identification of an orphan receptor gene as a type 1 calcitonin gene-related peptide receptor","volume":"217","author":"S Kapas","year":"1995","journal-title":"Biochem Bioph Res Co"},{"key":"pone.0285597.ref003","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2016.00224","article-title":"Atypical Chemokine Receptors and Their Roles in the Resolution of the inflammatory Response","volume":"7","author":"R Bonecchi","year":"2016","journal-title":"Front Immunol"},{"key":"pone.0285597.ref004","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.cyto.2018.02.024","article-title":"Emerging roles of atypical chemokine receptor 3 (ACKR3) in normal development and physiology","volume":"109","author":"KE Quinn","year":"2018","journal-title":"Cytokine"},{"issue":"9","key":"pone.0285597.ref005","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.1084\/jem.20052144","article-title":"A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development","volume":"203","author":"JM Burns","year":"2006","journal-title":"J Exp Med"},{"issue":"2","key":"pone.0285597.ref006","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1084\/jem.20102010","article-title":"CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity","volume":"208","author":"L Cruz-Orengo","year":"2011","journal-title":"Journal of Experimental Medicine"},{"issue":"5","key":"pone.0285597.ref007","doi-asserted-by":"crossref","first-page":"3204","DOI":"10.4049\/jimmunol.0900269","article-title":"Elucidation of CXCR7-mediated signaling events and inhibition of CXCR4-mediated tumor cell transendothelial migration by CXCR7 ligands","volume":"183","author":"BA Zabel","year":"2009","journal-title":"J Immunol"},{"key":"pone.0285597.ref008","article-title":"Control of chemokine-guided cell migration by ligand sequestration","volume":"132","author":"E Raz","year":"2008","journal-title":"Cell"},{"issue":"1","key":"pone.0285597.ref009","doi-asserted-by":"crossref","first-page":"3033","DOI":"10.1038\/s41467-020-16664-0","article-title":"The atypical chemokine receptor ACKR3\/CXCR7 is a broad-spectrum scavenger for opioid peptides","volume":"11","author":"M Meyrath","year":"2020","journal-title":"Nat Commun"},{"issue":"6","key":"pone.0285597.ref010","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1016\/j.cell.2013.10.052","article-title":"Modulation of circadian glucocorticoid oscillation via adrenal opioid-CXCR7 signaling alters emotional behavior","volume":"155","author":"Y Ikeda","year":"2013","journal-title":"Cell"},{"issue":"5","key":"pone.0285597.ref011","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/dvg.20387","article-title":"Early postnatal lethality and cardiovascular defects in CXCR7-deficient mice","volume":"46","author":"H Gerrits","year":"2008","journal-title":"Genesis"},{"issue":"37","key":"pone.0285597.ref012","doi-asserted-by":"crossref","first-page":"14759","DOI":"10.1073\/pnas.0702229104","article-title":"Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12\/SDF-1 receptor, CXCR7","volume":"104","author":"F Sierro","year":"2007","journal-title":"P Natl Acad Sci USA"},{"issue":"2","key":"pone.0285597.ref013","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1002\/dvdy.22549","article-title":"The Chemokine Receptor CXCR7 Functions to Regulate Cardiac Valve Remodeling","volume":"240","author":"SH Yu","year":"2011","journal-title":"Dev Dynam"},{"issue":"5","key":"pone.0285597.ref014","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/j.devcel.2014.07.012","article-title":"Decoy receptor CXCR7 modulates adrenomedullin-mediated cardiac and lymphatic vascular development","volume":"30","author":"KR Klein","year":"2014","journal-title":"Dev Cell"},{"issue":"3","key":"pone.0285597.ref015","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1093\/cvr\/cvn228","article-title":"Adrenomedullin induces lymphangiogenesis and ameliorates secondary lymphoedema","volume":"80","author":"D Jin","year":"2008","journal-title":"Cardiovasc Res"},{"issue":"12","key":"pone.0285597.ref016","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1016\/j.peptides.2008.09.009","article-title":"Adrenomedullin stabilizes the lymphatic endothelial barrier in vitro and in vivo","volume":"29","author":"WP Dunworth","year":"2008","journal-title":"Peptides"},{"key":"pone.0285597.ref017","doi-asserted-by":"crossref","first-page":"170347","DOI":"10.1016\/j.peptides.2020.170347","article-title":"Adrenomedullin\u2014Current perspective on a peptide hormone with significant therapeutic potential","volume":"131","author":"JP Fischer","year":"2020","journal-title":"Peptides"},{"issue":"11","key":"pone.0285597.ref018","doi-asserted-by":"crossref","DOI":"10.1242\/dev.167098","article-title":"When form meets function: the cells and signals that shape the lymphatic vasculature during development","volume":"148","author":"M Francois","year":"2021","journal-title":"Development"},{"key":"pone.0285597.ref019","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2019.00518","article-title":"The Interplay Between Lymphatic Vessels and Chemokines","volume":"10","author":"RH Farnsworth","year":"2019","journal-title":"Front Immunol"},{"issue":"16","key":"pone.0285597.ref020","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1101\/gad.303776.117","article-title":"Lymphangiogenesis guidance by paracrine and pericellular factors","volume":"31","author":"K Vaahtomeri","year":"2017","journal-title":"Gene Dev"},{"key":"pone.0285597.ref021","article-title":"CXCR7 Targeting and Its Major Disease Relevance","volume":"9","author":"C Wang","year":"2018","journal-title":"Front Pharmacol"},{"key":"pone.0285597.ref022","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.addr.2015.12.011","article-title":"Tumor lymphangiogenesis and new drug development","volume":"99","author":"LC Dieterich","year":"2016","journal-title":"Adv Drug Deliver Rev"},{"issue":"9","key":"pone.0285597.ref023","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1111\/bph.14132","article-title":"Different contributions of chemokine N-terminal features attest to a different ligand binding mode and a bias towards activation of ACKR3\/CXCR7 compared with CXCR4 and CXCR3","volume":"175","author":"M Szpakowska","year":"2018","journal-title":"Br J Pharmacol"},{"issue":"2","key":"pone.0285597.ref024","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1021\/acsptsci.1c00006","article-title":"Proadrenomedullin N-Terminal 20 Peptides (PAMPs) Are Agonists of the Chemokine Scavenger Receptor ACKR3\/CXCR7","volume":"4","author":"M Meyrath","year":"2021","journal-title":"ACS Pharmacol Transl Sci"},{"issue":"4","key":"pone.0285597.ref025","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0249068","article-title":"Lymphatic endothelial-cell expressed ACKR3 is dispensable for postnatal lymphangiogenesis and lymphatic drainage function in mice","volume":"16","author":"EC Sigmund","year":"2021","journal-title":"Plos One"},{"key":"pone.0285597.ref026","doi-asserted-by":"crossref","first-page":"14135","DOI":"10.1038\/ncomms14135","article-title":"Structural basis of ligand interaction with atypical chemokine receptor 3","volume":"8","author":"M Gustavsson","year":"2017","journal-title":"Nat Commun"},{"issue":"1","key":"pone.0285597.ref027","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1038\/s41467-021-21217-0","article-title":"LETR1 is a lymphatic endothelial-specific lncRNA governing cell proliferation and migration through KLF4 and SEMA3C","volume":"12","author":"L Ducoli","year":"2021","journal-title":"Nat Commun"},{"issue":"4","key":"pone.0285597.ref028","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.4049\/jimmunol.176.4.2197","article-title":"Expression and regulation of the orphan receptor RDC1 and its putative ligand in human dendritic and B cells","volume":"176","author":"S Infantino","year":"2006","journal-title":"J Immunol"},{"issue":"4","key":"pone.0285597.ref029","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1111\/j.1476-5381.2012.02202.x","article-title":"Receptor activity modifying proteins (RAMPs) interact with the VPAC2 receptor and CRF1 receptors and modulate their function","volume":"168","author":"D Wootten","year":"2013","journal-title":"Br J Pharmacol"},{"issue":"3","key":"pone.0285597.ref030","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1111\/j.1476-5381.2012.02197.x","article-title":"Receptor activity-modifying protein-dependent impairment of calcitonin receptor splice variant Delta(1\u201347)hCT((a)) function","volume":"168","author":"T Qi","year":"2013","journal-title":"Br J Pharmacol"},{"issue":"12","key":"pone.0285597.ref031","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1002\/psc.2833","article-title":"Fluorescently labeled adrenomedullin allows real-time monitoring of adrenomedullin receptor trafficking in living cells","volume":"21","author":"R Sch\u00f6nauer","year":"2015","journal-title":"J Pept Sci"},{"key":"pone.0285597.ref032","first-page":"1","article-title":"Characterization of a chimeric chemokine as a specific ligand for ACKR3","volume":"66","author":"R Ameti","year":"2018","journal-title":"J Leukoc Biol"},{"issue":"9","key":"pone.0285597.ref033","doi-asserted-by":"crossref","first-page":"5130","DOI":"10.4049\/jimmunol.1001660","article-title":"CXCR7 protein is not expressed on human or mouse leukocytes","volume":"185","author":"RD Berahovich","year":"2010","journal-title":"J Immunol"},{"key":"pone.0285597.ref034","doi-asserted-by":"crossref","DOI":"10.1038\/onc.2010.212","article-title":"Constitutive and chemokine-dependent internalization and recycling of CXCR7 in breast cancer cells to degrade chemokine ligands","volume":"29","author":"KE Luker","year":"2010","journal-title":"Oncogene"},{"issue":"38","key":"pone.0285597.ref035","doi-asserted-by":"crossref","first-page":"29602","DOI":"10.1074\/jbc.M004534200","article-title":"Visualization of the calcitonin receptor-like receptor and its receptor activity-modifying proteins during internalization and recycling","volume":"275","author":"K Kuwasako","year":"2000","journal-title":"J Biol Chem"},{"issue":"1","key":"pone.0285597.ref036","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1172\/JCI33302","article-title":"Adrenomedullin signaling is necessary for murine lymphatic vascular development","volume":"118","author":"KL Fritz-Six","year":"2008","journal-title":"J Clin Invest"},{"issue":"Suppl","key":"pone.0285597.ref037","doi-asserted-by":"crossref","first-page":"S93","DOI":"10.1291\/hypres.26.S93","article-title":"Adrenomedullin promotes proliferation and migration of cultured endothelial cells","volume":"26","author":"K Miyashita","year":"2003","journal-title":"Hypertens Res"},{"issue":"48","key":"pone.0285597.ref038","doi-asserted-by":"crossref","first-page":"24093","DOI":"10.1073\/pnas.1905561116","article-title":"RAMP3 determines rapid recycling of atypical chemokine receptor-3 for guided angiogenesis","volume":"116","author":"DI Mackie","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0285597.ref039","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.yjmcc.2014.09.017","article-title":"Functional differentiation of RAMP2 and RAMP3 in their regulation of the vascular system","volume":"77","author":"A Yamauchi","year":"2014","journal-title":"J Mol Cell Cardiol"},{"issue":"11","key":"pone.0285597.ref040","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1016\/S0196-9781(01)00532-0","article-title":"Adrenomedullin receptors: molecular identity and function","volume":"22","author":"DL Hay","year":"2001","journal-title":"Peptides"},{"issue":"6683","key":"pone.0285597.ref041","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/30666","article-title":"RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor","volume":"393","author":"LM McLatchie","year":"1998","journal-title":"Nature"},{"issue":"12","key":"pone.0285597.ref042","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.1084\/jem.187.12.2009","article-title":"Interferon-inducible T cell alpha chemoattractant (I-TAC): A novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3","volume":"187","author":"KE Cole","year":"1998","journal-title":"Journal of Experimental Medicine"},{"issue":"1","key":"pone.0285597.ref043","first-page":"643","article-title":"Cloning and Characterization of Cdna-Encoding a Precursor for Human Adrenomedullin (Vol 194, Pg 720, 1993)","volume":"202","author":"K Kitamura","year":"1994","journal-title":"Biochem Bioph Res Co"},{"issue":"4","key":"pone.0285597.ref044","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1016\/j.bbrc.2005.03.088","article-title":"Identification of MrgX2 as a human G-protein-coupled receptor for proadrenomedullin N-terminal peptides","volume":"330","author":"M Kamohara","year":"2005","journal-title":"Biochem Biophys Res Commun"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0285597","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,30]],"date-time":"2023-05-30T17:28:44Z","timestamp":1685467724000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0285597"}},"subtitle":[],"editor":[{"given":"Gabriella","family":"Lupo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,5,30]]},"references-count":44,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5,30]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0285597","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,30]]}}}