title: Extravillous Trophoblast and Endothelial Cell Crosstalk Mediates Leukocyte Infiltration to the Early Remodeling Decidual Spiral Arteriole Wall.
abstract: Decidual spiral arteriole (SpA) remodeling is essential to ensure optimal uteroplacental blood flow during human pregnancy, yet very little is known about the regulatory mechanisms. Uterine decidual NK (dNK) cells and macrophages infiltrate the SpAs and are proposed to initiate remodeling before colonization by extravillous trophoblasts (EVTs); however, the trigger for their infiltration is unknown. Using human first trimester placenta, decidua, primary dNK cells, and macrophages, we tested the hypothesis that EVTs activate SpA endothelial cells to secrete chemokines that have the potential to recruit maternal immune cells into SpAs. Gene array, real-time PCR, and ELISA analyses showed that treatment of endothelial cells with EVT conditioned medium significantly increased production of two chemokines, CCL14 and CXCL6. CCL14 induced chemotaxis of both dNK cells and decidual macrophages, whereas CXCL6 also induced dNK cell migration. Analysis of the decidua basalis from early pregnancy demonstrated expression of CCL14 and CXCL6 by endothelial cells in remodeling SpAs, and their cognate receptors are present in both dNK cells and macrophages. Neutralization studies identified IL-6 and CXCL8 as factors secreted by EVTs that induce endothelial cell CCL14 and CXCL6 expression. This study has identified intricate crosstalk between EVTs, SpA cells, and decidual immune cells that governs their recruitment to SpAs in the early stages of remodeling and has identified potential key candidate factors involved. This provides a new understanding of the interactions between maternal and fetal cells during early placentation and highlights novel avenues for research to understand defective SpA remodeling and consequent pregnancy pathology.
authors.affiliation: Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, United Kingdom; ruhul.choudhury@postgrad.manchester.ac.uk.|Academic Health Science Centre, St. Mary's Hospital, Manchester M13 9WL, United Kingdom.
authors.forename: Ruhul H
authors.initials: RH
authors.lastname: Choudhury
authors.affiliation: Research Centre for Women's and Infants' Health, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5T 3H7, Canada; and.
authors.forename: Caroline E
authors.identifier: 0000-0002-4146-099X
authors.initials: CE
authors.lastname: Dunk
authors.affiliation: Research Centre for Women's and Infants' Health, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5T 3H7, Canada; and.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lye
authors.affiliation: Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, United Kingdom.|Academic Health Science Centre, St. Mary's Hospital, Manchester M13 9WL, United Kingdom.
authors.forename: John D
authors.identifier: 0000-0001-8777-9261
authors.initials: JD
authors.lastname: Aplin
authors.affiliation: Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, United Kingdom.|Academic Health Science Centre, St. Mary's Hospital, Manchester M13 9WL, United Kingdom.|Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: Lynda K
authors.identifier: 0000-0001-7709-5202
authors.initials: LK
authors.lastname: Harris
authors.affiliation: Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, United Kingdom.|Academic Health Science Centre, St. Mary's Hospital, Manchester M13 9WL, United Kingdom.
authors.forename: Rebecca L
authors.identifier: 0000-0002-8871-0589
authors.initials: RL
authors.lastname: Jones
mesh_terms: D001160:Arterioles / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D054427:Chemokine CXCL6 / Q000096:biosynthesis / Q000276:immunology; D019742:Chemokines, CC / Q000096:biosynthesis / Q000276:immunology; D003470:Culture Media / Q000737:chemistry; D003656:Decidua / Q000276:immunology / Q000502:physiology*; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000502:physiology*; D008264:Macrophages / Q000276:immunology / Q000502:physiology*; D010920:Placenta / Q000166:cytology / Q000276:immunology; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D014327:Trophoblasts / Q000276:immunology / Q000378:metabolism*
chemical_list: C097720:CCL14 protein, human; C515503:CXCL6 protein, human; C508606:CXCL8 protein, human; D054427:Chemokine CXCL6; D019742:Chemokines, CC; D003470:Culture Media; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8