Inflammation-induced secretion of CCL21 in lymphatic endothelium is a key regulator of integrin-mediated dendritic cell transmigration
Abstract
Tissue inflammation induces rapid mobilization of antigen-charged dendritic cells (DCs), which migrate to draining lymph nodes via afferent lymphatics to elicit the immune response. This increase in DC trafficking has been shown to require integrin-dependent adhesion to ICAM-1 and VCAM-1, expressed on inflamed lymphatic endothelium. In addition, both constitutive- and inflammation-induced DC migration involves the chemokine CCL21, which most likely triggers integrin activation on DC via its receptor CCR7. Recently, however, conflicting evidence has suggested that DC entry occurs independently of integrins, implying that the role of CCL21 in lymphatics is purely chemotactic. Hence, while CCL21 is reported to be inducible during inflammation, the details of this induction and the role of CCL21 during initial DC trafficking are unclear. Here, we have characterized both the production of CCL21 and the mechanism of its action in DC transmigration using primary human dermal lymphatic endothelial cells (HDLECs) and a mouse model of skin contact hypersensitivity. We showed that CCL21 is constitutively expressed intracellularly but rapidly secreted after exposure to the inflammatory cytokine tumour necrosis factor (TNF) α following de novo RNA and protein synthesis. Furthermore, using in vitro transmigration assays, we showed that endogenous HDLEC-derived CCL21 stimulates DC translymphatic migration by a predominantly chemotactic mechanism in resting HDLEC and by a β2 integrin-mediated mechanism in TNFα-stimulated HDLEC. These results imply a direct role for CCL21 in lymphatic transmigration that involves the selective use of integrin activation in inflammation.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
CCL21 is the principal chemokine involved in the mobilization and entry of DCs and T cells into lymphatic capillaries.
“The principal chemokine involved in the mobilization and entry of DCs and T cells into lymphatic capillaries is CCL21 (97–99).”
From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [97]
The Introduction describes a role for CCL21 in DC entry into afferent lymphatics, and the section “Expression of CCL21 in inflamed lymphatics” (p. 845) calls it a key component of DC translymphatic migration. The paper does not establish CCL21 as the principal chemokine for both DCs and T cells entering lymphatic capillaries; its discussion of T-cell transmigration concerns vascular endothelium. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCCL21 is produced by LECs in initial LVs, and its synthesis is increased under inflammatory conditions.
“CCL21 is produced by LECs in initial LVs ( Figure 3a ), and its synthesis is increased under inflammatory conditions (97).”
From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [97]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium
Johnson, L. A., Clasper, S., Holt, A. P., Lalor, P. F., Baban, D., & Jackson, D. G. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20051759 · Cited by 346 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 3
- Luther, S. A., Tang, H. L., Hyman, P. L., Farr, A. G. and Cyster, J. G. 2000. Coexpression of the chemokines ELC and SLC by T zone stromal cells and deletion of the ELC gene in the plt/plt mouse. Proc. Natl Acad. Sci. USA 97:12694.
- Gunn, M. D., Tangemann, K., Tam, C., Cyster, J. G., Rosen, S. D. and Williams, L. T. 1998. A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc. Natl Acad. Sci. USA 95:258.
- Sligh, J. E., Ballantyne, C. M., Rich, S. S. et al. 1993. Inflammatory and immune responses are impaired in mice deficient in intercellular adhesion molecule 1. Proc. Natl Acad. Sci. USA 90:8529.
Cited by
Sorted by citations
Cancer stem cells as key drivers of tumour progression
Ayob, A. Z., & Ramasamy, T. S. (2018) · Journal of Biomedical Science · doi:10.1186/s12929-018-0426-4 · Cited by 910 · see citing works
Mosquera, J. V., Auguste, G., Wong, D., Turner, A. W., Hodonsky, C. J., Alvarez-Yela, A. C., Song, Y., Cheng, Q., Lino Cardenas, C. L., Theofilatos, K., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113380 · Cited by 123 · see citing works
Transport and Immune Functions of the Lymphatic System.
Davis, M. J., Zawieja, S. D., & King, P. D. (2025) · Annual Review of Physiology · doi:10.1146/annurev-physiol-022724-104908 · Cited by 42 · see citing works
- Authors
- Johnson, L. A., & Jackson, D. G.
- Affiliations
- John Radcliffe Hospital (GB)
- Venue
- International Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-08-25
- Volume
- 22
- Issue
- 10
- Pages
- 839-849
- ISSN
- 0953-8178 (ISSN-L)
- 1460-2377
- OpenAlex
- W2148371571
- Cited by
- 191
- References
- 1
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 14 · 2023: 11 · 2022: 13 · 2021: 14 · 2020: 10 · 2019: 12 · 2018: 13 · 2017: 9 · 2016: 8 · 2015: 8 · 2014: 17 · 2013: 14 · 2012: 9
- FWCI
- 5.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council
- Topics
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- CCL21, lymphatic endothelium, inflammation, integrin activation, beta2 integrins, CCR7, chemotaxis, TNF-α, lymphatic drainage, ICAM-1, VCAM-1
- MeSH terms
- Animals, Cell Movement, Cells, Cultured, Chemotaxis, Dendritic Cells, Dermatitis, Contact, Disease Models, Animal, Endothelium, Lymphatic, Gene Expression Regulation, Humans, Inflammation, Mice, Inbred BALB C, Skin, CD18 Antigens, Endothelial Cells, Mice, Chemokine CCL21
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
