title: Atypical chemokine receptor ACKR2 mediates chemokine scavenging by primary human trophoblasts and can regulate fetal growth, placental structure, and neonatal mortality in mice.
abstract: Inflammatory chemokines produced in the placenta can direct the migration of placental leukocytes using chemokine receptors that decorate the surface of these cells. Fetal trophoblasts can also express receptors for inflammatory chemokines, and they are one of the few cell types that express atypical chemokine receptor 2 (ACKR2), previously known as D6. ACKR2 binds many inflammatory CC chemokines but cannot stimulate cell migration or activate signaling pathways used by conventional chemokine receptors. Existing evidence suggests that ACKR2 is a specialized chemokine scavenger, but its function in primary human trophoblasts has not been explored. In mice, ACKR2 is thought to be dispensable for the reproductive success of unchallenged females that have conceived naturally, but it can suppress inflammation-induced abortion and aid the survival of implanted allogeneic embryos. In this article, we demonstrate that cultured primary human trophoblasts express ACKR2 far more strongly than genes encoding conventional receptors for inflammatory CC chemokines. Moreover, these cells are capable of the rapid internalization and efficient scavenging of extracellular chemokine, and this is mediated by ACKR2. We also report that in unchallenged DBA/1j mice, Ackr2 deficiency increases the incidence of stillbirth and neonatal death, leads to structural defects in the placenta, and can decrease fetal weight. Loss of Ackr2 specifically from fetal cells makes a key contribution to the placental defects. Thus, primary human trophoblasts use ACKR2 to scavenge chemokines, and ACKR2 deficiency can cause abnormal placental structure and reduced neonatal survival.
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, United Kingdom; School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom; and.
authors.forename: Pek Joo
authors.initials: PJ
authors.lastname: Teoh
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, United Kingdom; School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom; and.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Menzies
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, United Kingdom;
authors.forename: Chris A H
authors.initials: CA
authors.lastname: Hansell
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, United Kingdom;
authors.forename: Mairi
authors.initials: M
authors.lastname: Clarke
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, United Kingdom;
authors.forename: Carolann
authors.initials: C
authors.lastname: Waddell
authors.affiliation: Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, United Kingdom.
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Burton
authors.affiliation: School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom; and.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Nelson
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, United Kingdom; Robert.Nibbs@glasgow.ac.uk.
authors.forename: Robert J B
authors.initials: RJ
authors.lastname: Nibbs
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology; D000075906:Chemokine CCL26; D019742:Chemokines, CC / Q000235:genetics / Q000276:immunology; D005260:Female; D047109:Fetal Development; D005333:Fetus; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007223:Infant; D008136:Longevity; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010920:Placenta / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D061251:Primary Cell Culture; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D014327:Trophoblasts / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000097628:Chemokine Receptor D6
chemical_list: D018932:Chemokine CCL2; D000075906:Chemokine CCL26; D019742:Chemokines, CC; D019707:Receptors, Chemokine; C515708:ACKR2 protein, human; D000097628:Chemokine Receptor D6; C515709:Ackr2 protein, mouse; C111835:CCL2 protein, human; C120429:CCL26 protein, human; C492767:CCL3L1 protein, human