Met-Signaling Controls Dendritic Cell Migration in Skin by Regulating Podosome Formation and Function

Signaling through the HGF receptor/Met in skin-resident Langerhans cells (LCs) and dermal dendritic cells (DCs) is essential for their emigration toward draining lymph nodes upon inflammation-induced activation. In this study, we addressed the role of Met signaling in distinct steps of LC/dermal DC emigration from the skin by employing a conditionally Met-deficient mouse model (Metflox/flox). We found that Met deficiency severely impaired podosome formation in DCs and concomitantly decreased the proteolytic degradation of gelatin. Accordingly, Met-deficient LCs failed to efficiently cross the extracellular matrix-rich basement membrane between the epidermis and the dermis. We further observed that HGF-dependent Met activation reduced the adhesion of bone marrow-derived LCs to various extracellular matrix factors and enhanced the motility of DCs in three-dimensional collagen matrices, which was not the case for Met-deficient LCs/DCs. We found no impact of Met signaling on the integrin-independent amoeboid migration of DCs in response to the CCR7 ligand CCL19. Collectively, our data show that the Met-signaling pathway regulates the migratory properties of DC in HGF-dependent and HGF-independent manners.

Automated summary

This study investigates the importance of HGF receptor/Met signaling in the migration of skin-resident Langerhans cells (LCs) and dermal dendritic cells (DCs) towards draining lymph nodes. It demonstrates that Met deficiency impairs podosome formation and gelatin degradation in DCs, leading to inefficient crossing of the basement membrane. HGF-dependent Met activation reduces adhesion and enhances motility of DCs in collagen matrices, while Met signaling has no impact on integrin-independent amoeboid migration.