uPA-mediated remodeling of CCL21 gradients regulates lymphatic migration of dendritic cells

Victor Collado-Diaz; Maria-Nefeli Christakopoulou; Philipp Schineis; Katharina Blatter; David Laubender; Sébastien Trzebanski; Marina Thoma; Yves Gadient; Hazal Tatliadim; Konstantinos Gkelis; Mona C Friess; Vladimir Purvanov; Guerric P B Samson; Marc Artinger; Radjesh Bisoendial; Manuel Yepes; Simon J de Veer; David Craik; Niels Behrendt; Karina Silina; Daniel F Legler; Cornelia Halin

doi:10.1083/jcb.202412190

uPA-mediated remodeling of CCL21 gradients regulates lymphatic migration of dendritic cells

Victor Collado-Diaz^*, Maria-Nefeli Christakopoulou, Philipp Schineis, Katharina Blatter, David Laubender, Sébastien Trzebanski, Marina Thoma, Yves Gadient, Hazal Tatliadim, Konstantinos Gkelis, Mona C Friess, Vladimir Purvanov, Guerric P B Samson, Marc Artinger, Radjesh Bisoendial, Manuel Yepes, Simon J de Veer, David Craik, Niels Behrendt, Karina SilinaDaniel F Legler, Cornelia Halin

^*Corresponding author for this work

The Finsen Laboratory

Abstract

Dendritic cell (DC) migration via afferent lymphatics to draining LNs (dLNs) occurs in distinct steps that require the chemokine C-C motif ligand 21 (CCL21). In addition to full-length CCL21, which forms an immobilized perilymphatic gradient, a truncated soluble variant with enhanced gradient-forming capacity (CCL21-ΔC) was recently identified in tissues. We show that in skin, plasmin is continuously activated in a urokinase plasminogen activator (uPA)-dependent manner on lymphatic endothelial cells (LECs) and cleaves full-length CCL21, generating CCL21-ΔC. Inflammatory conditions, while promoting overall DC migration, markedly enhance this process, reducing immobilized perilymphatic CCL21 and increasing dermal CCL21-ΔC levels. Inhibition of uPA-mediated CCL21 cleavage causes full-length CCL21 to accumulate around dermal lymphatics, while CCL21-ΔC levels decline in the skin and dLN subcapsular sinus. Consequently, DC entry into afferent lymphatics is diminished, whereas DC egress from the subcapsular sinus into the LN parenchyma is enhanced. These findings reveal uPA/plasmin-dependent regulation of lymphatic CCL21 gradients and identify CCL21-ΔC as critical for DC migration.

Original language	English
Journal	Journal of Cell Biology
Volume	225
Issue number	3
ISSN	0021-9525
DOIs	https://doi.org/10.1083/jcb.202412190
Publication status	Published - 2 Mar 2026

Keywords

Chemokine CCL21/metabolism
Dendritic Cells/metabolism
Urokinase-Type Plasminogen Activator/metabolism
Animals
Cell Movement
Endothelial Cells/metabolism
Skin/metabolism
Mice, Inbred C57BL
Mice
Humans
Fibrinolysin/metabolism
Lymphatic Vessels
Lymph Nodes/metabolism

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Collado-Diaz, V., Christakopoulou, M.-N., Schineis, P., Blatter, K., Laubender, D., Trzebanski, S., Thoma, M., Gadient, Y., Tatliadim, H., Gkelis, K., Friess, M. C., Purvanov, V., Samson, G. P. B., Artinger, M., Bisoendial, R., Yepes, M., de Veer, S. J., Craik, D., Behrendt, N., ... Halin, C. (2026). uPA-mediated remodeling of CCL21 gradients regulates lymphatic migration of dendritic cells. Journal of Cell Biology, 225(3). https://doi.org/10.1083/jcb.202412190

Collado-Diaz, V, Christakopoulou, M-N, Schineis, P, Blatter, K, Laubender, D, Trzebanski, S, Thoma, M, Gadient, Y, Tatliadim, H, Gkelis, K, Friess, MC, Purvanov, V, Samson, GPB, Artinger, M, Bisoendial, R, Yepes, M, de Veer, SJ, Craik, D, Behrendt, N, Silina, K, Legler, DF & Halin, C 2026, 'uPA-mediated remodeling of CCL21 gradients regulates lymphatic migration of dendritic cells', Journal of Cell Biology, vol. 225, no. 3. https://doi.org/10.1083/jcb.202412190

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title = "uPA-mediated remodeling of CCL21 gradients regulates lymphatic migration of dendritic cells",

abstract = "Dendritic cell (DC) migration via afferent lymphatics to draining LNs (dLNs) occurs in distinct steps that require the chemokine C-C motif ligand 21 (CCL21). In addition to full-length CCL21, which forms an immobilized perilymphatic gradient, a truncated soluble variant with enhanced gradient-forming capacity (CCL21-ΔC) was recently identified in tissues. We show that in skin, plasmin is continuously activated in a urokinase plasminogen activator (uPA)-dependent manner on lymphatic endothelial cells (LECs) and cleaves full-length CCL21, generating CCL21-ΔC. Inflammatory conditions, while promoting overall DC migration, markedly enhance this process, reducing immobilized perilymphatic CCL21 and increasing dermal CCL21-ΔC levels. Inhibition of uPA-mediated CCL21 cleavage causes full-length CCL21 to accumulate around dermal lymphatics, while CCL21-ΔC levels decline in the skin and dLN subcapsular sinus. Consequently, DC entry into afferent lymphatics is diminished, whereas DC egress from the subcapsular sinus into the LN parenchyma is enhanced. These findings reveal uPA/plasmin-dependent regulation of lymphatic CCL21 gradients and identify CCL21-ΔC as critical for DC migration.",

keywords = "Chemokine CCL21/metabolism, Dendritic Cells/metabolism, Urokinase-Type Plasminogen Activator/metabolism, Animals, Cell Movement, Endothelial Cells/metabolism, Skin/metabolism, Mice, Inbred C57BL, Mice, Humans, Fibrinolysin/metabolism, Lymphatic Vessels, Lymph Nodes/metabolism",

author = "Victor Collado-Diaz and Maria-Nefeli Christakopoulou and Philipp Schineis and Katharina Blatter and David Laubender and S{\'e}bastien Trzebanski and Marina Thoma and Yves Gadient and Hazal Tatliadim and Konstantinos Gkelis and Friess, \{Mona C\} and Vladimir Purvanov and Samson, \{Guerric P B\} and Marc Artinger and Radjesh Bisoendial and Manuel Yepes and \{de Veer\}, \{Simon J\} and David Craik and Niels Behrendt and Karina Silina and Legler, \{Daniel F\} and Cornelia Halin",

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month = mar,

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doi = "10.1083/jcb.202412190",

language = "English",

volume = "225",

journal = "Journal of Cell Biology",

issn = "0021-9525",

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TY - JOUR

T1 - uPA-mediated remodeling of CCL21 gradients regulates lymphatic migration of dendritic cells

AU - Collado-Diaz, Victor

AU - Christakopoulou, Maria-Nefeli

AU - Schineis, Philipp

AU - Blatter, Katharina

AU - Laubender, David

AU - Trzebanski, Sébastien

AU - Thoma, Marina

AU - Gadient, Yves

AU - Tatliadim, Hazal

AU - Gkelis, Konstantinos

AU - Friess, Mona C

AU - Purvanov, Vladimir

AU - Samson, Guerric P B

AU - Artinger, Marc

AU - Bisoendial, Radjesh

AU - Yepes, Manuel

AU - de Veer, Simon J

AU - Craik, David

AU - Behrendt, Niels

AU - Silina, Karina

AU - Legler, Daniel F

AU - Halin, Cornelia

PY - 2026/3/2

Y1 - 2026/3/2

N2 - Dendritic cell (DC) migration via afferent lymphatics to draining LNs (dLNs) occurs in distinct steps that require the chemokine C-C motif ligand 21 (CCL21). In addition to full-length CCL21, which forms an immobilized perilymphatic gradient, a truncated soluble variant with enhanced gradient-forming capacity (CCL21-ΔC) was recently identified in tissues. We show that in skin, plasmin is continuously activated in a urokinase plasminogen activator (uPA)-dependent manner on lymphatic endothelial cells (LECs) and cleaves full-length CCL21, generating CCL21-ΔC. Inflammatory conditions, while promoting overall DC migration, markedly enhance this process, reducing immobilized perilymphatic CCL21 and increasing dermal CCL21-ΔC levels. Inhibition of uPA-mediated CCL21 cleavage causes full-length CCL21 to accumulate around dermal lymphatics, while CCL21-ΔC levels decline in the skin and dLN subcapsular sinus. Consequently, DC entry into afferent lymphatics is diminished, whereas DC egress from the subcapsular sinus into the LN parenchyma is enhanced. These findings reveal uPA/plasmin-dependent regulation of lymphatic CCL21 gradients and identify CCL21-ΔC as critical for DC migration.

AB - Dendritic cell (DC) migration via afferent lymphatics to draining LNs (dLNs) occurs in distinct steps that require the chemokine C-C motif ligand 21 (CCL21). In addition to full-length CCL21, which forms an immobilized perilymphatic gradient, a truncated soluble variant with enhanced gradient-forming capacity (CCL21-ΔC) was recently identified in tissues. We show that in skin, plasmin is continuously activated in a urokinase plasminogen activator (uPA)-dependent manner on lymphatic endothelial cells (LECs) and cleaves full-length CCL21, generating CCL21-ΔC. Inflammatory conditions, while promoting overall DC migration, markedly enhance this process, reducing immobilized perilymphatic CCL21 and increasing dermal CCL21-ΔC levels. Inhibition of uPA-mediated CCL21 cleavage causes full-length CCL21 to accumulate around dermal lymphatics, while CCL21-ΔC levels decline in the skin and dLN subcapsular sinus. Consequently, DC entry into afferent lymphatics is diminished, whereas DC egress from the subcapsular sinus into the LN parenchyma is enhanced. These findings reveal uPA/plasmin-dependent regulation of lymphatic CCL21 gradients and identify CCL21-ΔC as critical for DC migration.

KW - Chemokine CCL21/metabolism

KW - Dendritic Cells/metabolism

KW - Urokinase-Type Plasminogen Activator/metabolism

KW - Animals

KW - Cell Movement

KW - Endothelial Cells/metabolism

KW - Skin/metabolism

KW - Mice, Inbred C57BL

KW - Mice

KW - Humans

KW - Fibrinolysin/metabolism

KW - Lymphatic Vessels

KW - Lymph Nodes/metabolism

UR - https://www.scopus.com/pages/publications/105028803684

U2 - 10.1083/jcb.202412190

DO - 10.1083/jcb.202412190

M3 - Journal article

C2 - 41591762

SN - 0021-9525

VL - 225

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 3

ER -

uPA-mediated remodeling of CCL21 gradients regulates lymphatic migration of dendritic cells

Abstract

Keywords

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