Chemokine scavenger D6 is expressed by trophoblasts and aids the survival of mouse embryos transferred into allogeneic recipients.
Proinflammatory CC chemokines are thought to drive recruitment of maternal leukocytes into gestational tissues and regulate extravillous trophoblast migration. The atypical chemokine receptor D6 binds many of these chemokines and is highly expressed by the human placenta. D6 is thought to act as a chemokine scavenger because, when ectopically expressed in cell lines in vitro, it efficiently internalizes proinflammatory CC chemokines and targets them for destruction in the absence of detectable chemokine-induced signaling. Moreover, D6 suppresses inflammation in many mouse tissues, and notably, D6-deficient fetuses in D6-deficient female mice show increased susceptibility to inflammation-driven resorption. In this paper, we report strong anti-D6 immunoreactivity, with specific intracellular distribution patterns, in trophoblast-derived cells in human placenta, decidua, and gestational membranes throughout pregnancy and in trophoblast disease states of hydatidiform mole and choriocarcinoma. We show, for the first time, that endogenous D6 in a human choriocarcinoma-derived cell line can mediate progressive chemokine scavenging and that the D6 ligand CCL2 can specifically associate with human syncytiotrophoblasts in term placenta in situ. Moreover, despite strong chemokine production by gestational tissues, levels of D6-binding chemokines in maternal plasma decrease during pregnancy, even in women with pre-eclampsia, a disease associated with increased maternal inflammation. In mice, D6 is not required for syngeneic or semiallogeneic fetal survival in unchallenged mice, but interestingly, it does suppress fetal resorption after embryo transfer into fully allogeneic recipients. These data support the view that trophoblast D6 scavenges maternal chemokines at the fetomaternal interface and that, in some circumstances, this can help to ensure fetal survival.
Madigan
Judith
J
Division of Immunology, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, United Kingdom.
Freeman
Dilys J
DJ
Menzies
Fiona
F
Forrow
Steve
S
Nelson
Scott M
SM
Young
Anne
A
Sharkey
Andrew
A
Moffett
Ashley
A
Graham
Gerard J
GJ
Greer
Ian A
IA
Rot
Antal
A
Nibbs
Robert J B
RJ
D000818:Animals; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000097:blood; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004624:Embryo Transfer / Q000009:adverse effects / Q000401:mortality; D004622:Embryo, Mammalian / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006085:Graft Survival / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D008297:Male; D008431:Maternal-Fetal Exchange / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011225:Pre-Eclampsia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D011247:Pregnancy; D011256:Pregnancy Outcome / Q000235:genetics; D011257:Pregnancy Proteins / Q000096:biosynthesis / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D054447:Receptors, CCR10 / Q000096:biosynthesis / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D014184:Transplantation, Homologous / Q000401:mortality; D014327:Trophoblasts / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D000097628:Chemokine Receptor D6
D018932:Chemokine CCL2; D018836:Inflammation Mediators; D011257:Pregnancy Proteins; D054447:Receptors, CCR10; D000097628:Chemokine Receptor D6; C111835:CCL2 protein, human