title: D6 facilitates cellular migration and fluid flow to lymph nodes by suppressing lymphatic congestion.
abstract: Lymphatic endothelial cells are important for efficient flow of antigen-bearing fluid and antigen-presenting cells (APCs) from peripheral sites to lymph nodes (LNs). APC movement to LNs is dependent on the constitutive chemokine receptor CCR7, although how conflicting inflammatory and constitutive chemokine cues are integrated at lymphatic surfaces during this process is not understood. Here we reveal a previously unrecognized aspect of the regulation of this process. The D6 chemokine-scavenging receptor, which is expressed on lymphatic endothelial cells (LECs), maintains lymphatic surfaces free of inflammatory CC-chemokines and minimizes interaction of inflammatory leukocytes with these surfaces. D6 does not alter the level of CCR7 ligands on LECs, thus ensuring selective presentation of homeostatic chemokines for interaction with CCR7(+) APCs. Accordingly, in D6-deficient mice, inflammatory CC-chemokine adherence to LECs results in inappropriate perilymphatic accumulation of inflammatory leukocytes at peripheral inflamed sites and draining LNs. This results in lymphatic congestion and impaired movement of APCs, and fluid, from inflamed sites to LNs. We propose that D6, by suppressing inflammatory chemokine binding to lymphatic surfaces, and thereby preventing inappropriate inflammatory leukocyte adherence, is a key regulator of lymphatic function and a novel, and indispensable, contributor to the integration of innate and adaptive immune responses.
authors: Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom.
authors: Kit Ming
authors: KM
authors: Lee
authors: Clive S
authors: CS
authors: McKimmie
authors: Derek S
authors: DS
authors: Gilchrist
authors: Kenneth J
authors: KJ
authors: Pallas
authors: Robert J
authors: RJ
authors: Nibbs
authors: Paul
authors: P
authors: Garside
authors: Victoria
authors: V
authors: McDonald
authors: Christopher
authors: C
authors: Jenkins
authors: Richard
authors: R
authors: Ransohoff
authors: Liping
authors: L
authors: Liu
authors: Simon
authors: S
authors: Milling
authors: Vuk
authors: V
authors: Cerovic
authors: Gerard J
authors: GJ
authors: Graham
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology; D001826:Body Fluids / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology*; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism; D018946:Chemokine CCL5 / Q000276:immunology / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology; D007962:Leukocytes / Q000166:cytology / Q000276:immunology; D008196:Lymph / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D054390:Receptors, CCR2 / Q000276:immunology / Q000378:metabolism; D054400:Receptors, CCR7 / Q000276:immunology / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology*; D000097628:Chemokine Receptor D6
chemical_list: D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054390:Receptors, CCR2; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; C515709:Ackr2 protein, mouse; D000097628:Chemokine Receptor D6; C491768:Ccl2 protein, mouse; C503460:Ccl5 protein, mouse; C515335:Ccr2 protein, mouse; C515371:Ccr7 protein, mouse