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The chemokine receptors ACKR 2 and CCR 2 reciprocally regulate lymphatic vessel density
Author(s) -
Lee Kit M,
Danuser Renzo,
Stein Jens V,
Graham Delyth,
Nibbs Robert JB,
Graham Gerard J
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201488887
Subject(s) - biology , chemokine receptor , receptor , microbiology and biotechnology , lymphatic vessel , chemokine , lymphatic system , immunology , biochemistry , genetics , cancer , metastasis
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, ACKR 2, 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 CCL 2, which is scavenged by ACKR 2, are associated with this phenotype. Accordingly, mice deficient for the CCL 2 signalling receptor, CCR 2, 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 ACKR 2‐deficient mice and reduced in CCR 2‐deficient mice. Therefore, these receptors regulate vessel density by reciprocally modulating pro‐lymphangiogenic macrophage recruitment, and proximity, to developing, resting and regenerating lymphatic vessels.