HGF/Met-Signaling Contributes to Immune Regulation by Modulating Tolerogenic and Motogenic Properties of Dendritic Cells

Abstract

Hepatocyte growth factor (HGF)-signaling via Met can induce mitogenic, morphogenic, and motogenic activity in various cell types. Met expression in the immune system is limited to cells with antigen-presenting capacities, including dendritic cells (DCs). Thus, it appears highly conceivable that Met-signaling impacts on adaptive immune responses. However, the mechanisms by which HGF imparts its effects on immunological responses are not yet fully understood. DCs possess unique functionalities that are critically involved in controlling both tolerance and immunity. HGF conveys immunoregulatory functions, which strongly correlate with that of DCs orchestrating the apt immune response in inflammation. Therefore, this review focuses on the current knowledge of Met-signaling in DCs with specific emphasis on the morphogenic and motogenic activities. HGF has been identified to play a role in peripheral immune tolerance by directing DC differentiation towards a tolerogenic phenotype. In skin immunity, Met-signaling was shown to drive mobilization of DCs by regulating matrix metalloproteinase activities. This is strikingly reminiscent of the role of Met for regulating a cell fate program during embryonic development, wound healing, and in tumor invasion known as epithelial-mesenchymal transition (EMT). Thus, the concept emerges that an EMT program is executed by Met-signaling in DCs, which will be also discussed.

Keywords: HGF; Langerhans cells; MMPs; Met; dendritic cells; epithelial-mesenchymal transition; immune tolerance; immune-based therapies; migration.

Figure 1

Hepatocyte growth factor (HGF)/Met-signaling in dendritic cells (DCs). Schematic representation of the motogenic and morphogenic activities of Met-signaling on DCs in peripheral and lymphoid tissues. DC precursors originating from hematopoietic stem cells (HSC) in bone marrow (BM) migrate towards peripheral tissues such as the skin. Upon activation DCs/Langerhans cells (LCs) migrate via lymphatics to draining lymph nodes to present antigens to naive T cells. Met-signaling induces LC and DC emigration from skin in an epithelial-mesenchymal transition (EMT)-like process, including matrix metalloproteinases (MMP) activation. HGF-induced morphogenic activities include induction of a tolerogenic phenotype of DCs by IL-10 secretion and upregulated expression of, e.g., glucocorticoid-induced leucine zipper (GILZ) and programmed-death ligand 1 (PD-L1), which finally results in enhanced numbers of Tregs.