Summary diagram. Summary of the main findings and the overall model. Top: Summary of events happening at the level of LECs: continuous low-level extravasation of plasminogen from blood vessels leads to uPA/uPAR-mediated activation of plasmin, which in turn cleaves immobilized CCL21 into soluble CCL21-ΔC (WT steady-state—left). When uPA-mediated activation of plasminogen is compromised (uPA^mut), less CCL21 gets cleaved, shifting the balance toward more immobilized CCL21 accumulating on/around LECs (uPA^mut steady-state—middle). Under inflammatory conditions, with higher extravasation of plasminogen and higher expression of uPA and uPAR by LECs, more plasmin is activated, resulting in more CCL21 cleavage (WT inflammation—right). Bottom: The bottom part of the figure illustrates how these changes affect the balance between immobilized CCL21 and soluble CCL21-ΔC around afferent lymphatics and in the dLN. Additionally, the impact on distinct CCR7-dependent steps (1–3) in lymphatic migration of DCs are indicated. Question marks (?) indicate steps that were not specifically investigated in this study and thus represent speculations based on indirect findings and/or the literature.