Cited by 71Chemokine receptors and signalingLymphatic System and DiseasesImmune Response and Inflammation

ACKR4 on stromal cells scavenges CCL19 to enable CCR7-dependent trafficking of APCs from inflamed skin to lymph nodes

Bryce, Steven A, Wilson, Ruairi A M, Tiplady, Eleanor M, Asquith, Darren L, Bromley, Shannon K, Luster, Andrew D, Graham, Gerard J, Nibbs, Robert J B·2016·The Journal of Immunology

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…

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Crossref · 10.4049/jimmunol.1501542

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  • The impaired DC migration in ACKR4-deficient mice can be rescued by codisruption of the gene encoding CCL19.

    “Curiously, the impaired migration can be rescued by codisruption of the gene that encodes the CCL19 chemokine that is normally produced by DCs themselves and fibroblasts and which also binds CCR7 (105).”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [105]

  • Gradients of CCL21 are maintained by the ACKR4 scavenger receptor expressed by stromal cells in the interstitium.

    “Gradients of CCL21 are maintained by the ACKR4 scavenger receptor that is expressed by stromal cells in the interstitium (104, 105).”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [105]

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Authors
Bryce, S. A., Wilson, R. A. M., Tiplady, E. M., Asquith, D. L., Bromley, S. K., Luster, A. D., Graham, G. J., & Nibbs, R. J. B.
Affiliations
  • University of Glasgow (GB)
  • Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow G12 8TA ,
  • Harvard University (US)
Corresponding author
Nibbs, Robert J B
Venue
The Journal of Immunology
Published
2016-04
Volume
196
Issue
8
Pages
3341-3353
ISSN
  • 0022-1767 (ISSN-L)
  • 1550-6606
OpenAlex
W2305178018
Cited by
71
References
42
Citations by year
2026: 5 · 2025: 2 · 2024: 13 · 2023: 8 · 2022: 7 · 2021: 11 · 2020: 5 · 2019: 8 · 2018: 8 · 2017: 3 · 2016: 1
FWCI
3.59
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
Funders
  • Cancer Research Institute
  • Cancer Research UK (C596A17196, C596/A18076)
  • University of Glasgow
  • Medical Research Council (MR/M019764/1)
  • Biotechnology and Biological Sciences Research Council (1371671)
  • Beatson Institute for Cancer Research
Topics
  • Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
ACKR4, CCL19, CCL21, CCR7, Langerhans cells, dermal dendritic cells, skin-draining lymph nodes, chemokine scavenging, keratinocytes, skin inflammation, subcapsular sinus
MeSH terms
Animals, Cell Movement, Dendritic Cells, Inflammation, Lymph Nodes, Male, Mice, Inbred C57BL, Skin, Keratinocytes, Stromal Cells, Mice, Knockout, Protein Transport, Endothelial Cells, Mice, Receptors, CCR, Receptors, CCR7, Chemokine CCL19, Chemokine CCL21

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