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
N1 - Publisher Copyright:
© 2026 Collado-Diaz et al.
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.
UR - https://www.scopus.com/pages/publications/105028803684
U2 - 10.1083/jcb.202412190
DO - 10.1083/jcb.202412190
M3 - Article
C2 - 41591762
AN - SCOPUS:105028803684
SN - 0021-9525
VL - 225
JO - The Journal of cell biology
JF - The Journal of cell biology
IS - 3
ER -