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

## TL;DR

The paper shows how a protein called uPA helps reshape chemokine gradients in the lymphatic system, which controls how immune cells called dendritic cells move.

## Contribution

The study identifies a proteolytic mechanism involving uPA/plasmin that regulates CCL21 gradients and dendritic cell migration.

## Key findings

- uPA-dependent cleavage of CCL21 by plasmin generates a soluble variant, CCL21-ΔC, in lymphatic endothelial cells.
- Inhibition of uPA-mediated cleavage disrupts normal dendritic cell migration into and out of lymphatic structures.
- Inflammatory conditions enhance uPA activity, altering CCL21 gradients and dendritic cell positioning.

## Abstract

Collado-Diaz et al., show that lymphatic endothelial cells generate a soluble chemokine variant, CCL21-ΔC, through uPA/plasmin-dependent cleavage. This process reshapes chemokine gradients in skin and LNs, thereby regulating dendritic cell migration and positioning and uncovering a proteolytic mechanism that fine-tunes immune surveillance.

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.