title: ACKR4 on Stromal Cells Scavenges CCL19 To Enable CCR7-Dependent Trafficking of APCs from Inflamed Skin to Lymph Nodes.
abstract: Dermal dendritic cells and epidermal Langerhans cells are APCs that migrate from skin to draining lymph nodes (LN) to drive peripheral tolerance and adaptive immunity. Their migration requires the chemokine receptor CCR7, which directs egress from the skin via dermal lymphatic vessels and extravasation into the LN parenchyma from lymph in the subcapsular sinus. CCR7 is activated by two chemokines: CCL19 and CCL21. CCL21 alone is sufficient for the migration of APCs from skin to LN. CCL19 and CCL21 also bind atypical chemokine receptor (ACKR) 4. ACKR4-mediated CCL21 scavenging by lymphatic endothelial cells lining the subcapsular sinus ceiling stabilizes interfollicular CCL21 gradients that direct lymph-borne CCR7(+)APCs into the parenchyma of mouse LN. In this study, we show that ACKR4 also aids APC egress from mouse skin under steady-state and inflammatory conditions. ACKR4 plays a particularly prominent role during cutaneous inflammation when it facilitates Langerhans cell egress from skin and enables the accumulation of dermal dendritic cells in skin-draining LN. Stromal cells in mouse skin, predominantly keratinocytes and a subset of dermal lymphatic endothelial cells, express ACKR4 and are capable of ACKR4-dependent chemokine scavenging in situ. ACKR4-mediated scavenging of dermal-derived CCL19, rather than CCL21, is critical during inflammation, because the aberrant trafficking of skin-derived APCs inAckr4-deficient mice is completely rescued by genetic deletion ofCcl19 Thus, ACKR4 on stromal cells aids the egress of APCs from mouse skin, and, during inflammation, facilitates CCR7-dependent cell trafficking by scavenging CCL19.
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom; and.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Bryce
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom; and.
authors.forename: Ruairi A M
authors.identifier: http://orcid.org/0000-0002-0970-5475
authors.initials: RA
authors.lastname: Wilson
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom; and.
authors.forename: Eleanor M
authors.identifier: http://orcid.org/0000-0002-2983-0134
authors.initials: EM
authors.lastname: Tiplady
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom; and.
authors.forename: Darren L
authors.initials: DL
authors.lastname: Asquith
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
authors.forename: Shannon K
authors.identifier: http://orcid.org/0000-0002-5400-896X
authors.initials: SK
authors.lastname: Bromley
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom; and.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Graham
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom; and robert.nibbs@glasgow.ac.uk.
authors.forename: Robert J B
authors.initials: RJ
authors.lastname: Nibbs
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology; D054415:Chemokine CCL19 / Q000235:genetics / Q000378:metabolism*; D054421:Chemokine CCL21 / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D042783:Endothelial Cells / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D015603:Keratinocytes / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021381:Protein Transport / Q000276:immunology; D054388:Receptors, CCR / Q000235:genetics / Q000378:metabolism*; D054400:Receptors, CCR7 / Q000378:metabolism*; D012867:Skin / Q000276:immunology / Q000473:pathology*; D017154:Stromal Cells / Q000276:immunology
chemical_list: C000593439:Ackr4 protein, mouse; C515461:Ccl19 protein, mouse; C515371:Ccr7 protein, mouse; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D054388:Receptors, CCR; D054400:Receptors, CCR7