The HGF receptor/Met tyrosine kinase is a key regulator of dendritic cell migration in skin immunity.
The Met tyrosine kinase has a pivotal role in embryonic development and tissue regeneration, and deregulated Met signaling contributes to tumorigenesis. After binding of its cognate ligand hepatocyte growth factor, Met signaling confers mitogenic, morphogenic, and motogenic activity to various cells. Met expression in the hematopoietic compartment is limited to progenitor cells and their Ag-presenting progeny, including dendritic cells (DCs). In this study, we demonstrate that Met signaling in skin-resident DCs is essential for their emigration toward draining lymph nodes upon inflammation-induced activation. By using a conditional Met-deficient mouse model (Met(flox/flox)), we show that Met acts on the initial step of DC release from skin tissue. Met-deficient DCs fail to reach skin-draining lymph nodes upon activation while exhibiting an activated phenotype. Contact hypersensitivity reactions in response to various contact allergens is strongly impaired in Met-deficient mice. Inhibition of Met signaling by single-dose epicutaneous administration of the Met kinase-specific inhibitor SU11274 also suppressed contact hypersensitivity in wild-type mice. Additionally, we found that Met signaling regulates matrix metalloproteinase MMP2 and MMP9 activity, which is important for DC migration through extracellular matrix. These data unveil Met signaling in DCs as a critical determinant for the maintenance of normal immune function and suggest Met as a potential target for treatment of autoimmune skin diseases.
Department of Cell Biology, Institute for Biomedical Engineering, Medical Faculty, Rheinisch-Westfälische Technische Hochschule, 52074 Aachen, Germany.
Jea-Hyun
JH
Baek
Carmen
C
Birchmeier
Martin
M
Zenke
Thomas
T
Hieronymus
D000818:Animals; D002465:Cell Movement / Q000276:immunology*; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology*; D005434:Flow Cytometry; D015151:Immunoblotting; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D019859:Proto-Oncogene Proteins c-met / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000276:immunology*
D019859:Proto-Oncogene Proteins c-met