The chemokine receptors ACKR2 and CCR2 reciprocally regulate lymphatic vessel density

Lee, K. M., Danuser, R., Stein, J. V., Graham, D. , Nibbs, R. J.B. and Graham, G. J. (2014) The chemokine receptors ACKR2 and CCR2 reciprocally regulate lymphatic vessel density. EMBO Journal, 33(21), pp. 2564-2580. (doi:10.15252/embj.201488887)

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Publisher's URL: http://dx.doi.org/10.15252/embj.201488887

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Graham, Dr Delyth and Nibbs, Professor Rob and Lee, Miss Kit and Graham, Professor Gerard
Authors: Lee, K. M., Danuser, R., Stein, J. V., Graham, D., Nibbs, R. J.B., and Graham, G. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:EMBO Journal
Publisher:EMBO Press
ISSN:0261-4189
ISSN (Online):1460-2075
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in EMBO Journal 33(21):2564-2580
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
514422Regulation of the adaptive immune response by chemokine scavenging receptorsGerard GrahamMedical Research Council (MRC)G0901113III -IMMUNOLOGY