title: The chemokine receptors ACKR2 and CCR2 reciprocally regulate lymphatic vessel density.
abstract: Macrophages regulate lymphatic vasculature development; however, the molecular mechanisms regulating their recruitment to developing, and adult, lymphatic vascular sites are not known. Here, we report that resting mice deficient for the inflammatory chemokine-scavenging receptor, ACKR2, display increased lymphatic vessel density in a range of tissues under resting and regenerating conditions. This appears not to alter dendritic cell migration to draining lymph nodes but is associated with enhanced fluid drainage from peripheral tissues and thus with a hypotensive phenotype. Examination of embryonic skin revealed that this lymphatic vessel density phenotype is developmentally established. Further studies indicated that macrophages and the inflammatory CC-chemokine CCL2, which is scavenged by ACKR2, are associated with this phenotype. Accordingly, mice deficient for the CCL2 signalling receptor, CCR2, displayed a reciprocal phenotype of reduced lymphatic vessel density. Further examination revealed that proximity of pro-lymphangiogenic macrophages to developing lymphatic vessel surfaces is increased in ACKR2-deficient mice and reduced in CCR2-deficient mice. Therefore, these receptors regulate vessel density by reciprocally modulating pro-lymphangiogenic macrophage recruitment, and proximity, to developing, resting and regenerating lymphatic vessels.
authors.affiliation: Institute of Infection, Immunity and Inflammation College of Medical, Veterinary and Life Sciences University of Glasgow, Glasgow, UK.
authors.forename: Kit M
authors.initials: KM
authors.lastname: Lee
authors.affiliation: Theodor Kocher Institute University of Bern, Bern, Switzerland.
authors.forename: Renzo
authors.initials: R
authors.lastname: Danuser
authors.affiliation: Theodor Kocher Institute University of Bern, Bern, Switzerland.
authors.forename: Jens V
authors.initials: JV
authors.lastname: Stein
authors.affiliation: Institute of Cardiovascular and Medical Sciences College of Medical, Veterinary and Life Sciences University of Glasgow, Glasgow, UK.
authors.forename: Delyth
authors.initials: D
authors.lastname: Graham
authors.affiliation: Institute of Infection, Immunity and Inflammation College of Medical, Veterinary and Life Sciences University of Glasgow, Glasgow, UK.
authors.forename: Robert J B
authors.initials: RJ
authors.lastname: Nibbs
authors.affiliation: Institute of Infection, Immunity and Inflammation College of Medical, Veterinary and Life Sciences University of Glasgow, Glasgow, UK Gerard.graham@glasgow.ac.uk.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Graham
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology*; D008198:Lymph Nodes / Q000166:cytology / Q000196:embryology; D042583:Lymphangiogenesis / Q000502:physiology*; D042601:Lymphatic Vessels / Q000166:cytology / Q000196:embryology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000166:cytology / Q000196:embryology; D000097628:Chemokine Receptor D6
chemical_list: D054390:Receptors, CCR2; D019707:Receptors, Chemokine; C515709:Ackr2 protein, mouse; D000097628:Chemokine Receptor D6; C515335:Ccr2 protein, mouse
keywords: atypical receptors; chemokine; development; lymphatic; macrophage