uPA-mediated remodeling of CCL21 gradients regulates lymphatic migration of dendritic cells
Year: 2025
Type: article
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.
Source: The Journal of Cell Biology
Authors: 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
Institutions: Universitat de València, ETH Zurich, Institute of Pharmaceutical Sciences, Max Planck Institute for Biological Intelligence, University of Konstanz, Institute of Cell Biology and Immunology Thurgau, Erasmus MC, Maasstad Ziekenhuis, Emory University, The University of Queensland, ARC Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, University of Copenhagen, Rigshospitalet, University of Bern
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W7125797698