Placental chemokine compartmentalisation: a novel mammalian molecular control mechanism

Lee, K. M., Wilson, G. J. , Pingen, M., Fukuoka, A. , Hansell, C. A.H., Bartolini, R., Medina-Ruiz, L. and Graham, G. J. (2019) Placental chemokine compartmentalisation: a novel mammalian molecular control mechanism. PLoS Biology, 17(5), e3000287. (doi: 10.1371/journal.pbio.3000287) (PMID:31141500) (PMCID:PMC6557524)

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Abstract

Atypical chemokine receptor 2 (ACKR2) is a chemokine-scavenging receptor. ACKR2–/–embryos display a reduction in size of a novel, to our knowledge, embryonic skin macrophage population referred to as ‘intermediate’ cells. CC chemokine receptor 2 (CCR2)–/–embryos display an identical phenotype, indicating that these cells require CCR2 to enable them to populate embryonic skin. Further analysis revealed that ACKR2–/–embryos have higher circulating concentrations of the CCR2 ligand, CC ligand 2 (CCL2); thus, ACKR2 regulates intraembryonic CCL2 levels. We show that ACKR2 is strongly expressed by trophoblasts and that it blocks movement of inflammatory chemokines, such as CCL2, from the maternal decidua into the embryonic circulation. We propose that trophoblastic ACKR2 is responsible for ensuring chemokine compartmentalisation on the maternal decidua, without which chemokines enter the embryonic circulation, disrupting gradients essential for directed intraembryonic cell migration. Overall, therefore, we describe a novel, to our knowledge, molecular mechanism whereby maternal decidual chemokines can function in a compartmentalised fashion without interfering with intraembryonic leukocyte migration. These data suggest similar functions for other atypical chemokine receptors in the placenta and indicate that defects in such receptors may have unanticipated developmental consequences.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Suzuki, Dr Ayumi and Wilson, Dr Gillian and Lee, Miss Kit and Hansell, Dr Chris and Pingen, Dr Marieke and Medina-Ruiz, Dr Laura and Bartolini, Mr Robin and Graham, Professor Gerard
Creator Roles:
Lee, K. M.Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review and editing
Wilson, G. J.Formal analysis, Investigation, Writing – original draft, Writing – review and editing
Pingen, M.Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review and editing
Hansell, C. A.H.Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review and editing
Bartolini, R.Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review and editing
Medina-Ruiz, L.Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review and editing
Graham, G. J.Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Writing – original draft, Writing – review and editing
Fukuoka, A.Formal analysis, Methodology, Writing – review and editing
Authors: Lee, K. M., Wilson, G. J., Pingen, M., Fukuoka, A., Hansell, C. A.H., Bartolini, R., Medina-Ruiz, L., and Graham, G. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Biology
Publisher:Public Library of Science
ISSN:1544-9173
ISSN (Online):1545-7885
Published Online:29 May 2019
Copyright Holders:Copyright © 2019 Lee et al.
First Published:First published in PLoS Biology 17(5): e3000287
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
681091The ACKR2-CCR2 axis in development and diseaseGerard GrahamMedical Research Council (MRC)MR/M019764/1III -IMMUNOLOGY
600961Dissecting the chemokine basis for the orchestration of the in vivo inflammatory responseGerard GrahamWellcome Trust (WELLCOTR)099251/Z/12/ZIII -IMMUNOLOGY