VEGF-A promotes IL-17A-producing γδ T cell accumulation in mouse skin and serves as a chemotactic factor for plasmacytoid dendritic cells.
BACKGROUND
IL-17-producing CD4(+) T (Th17) cells and their cytokines, IL-17A and IL-22, are deeply involved in the pathogenesis of psoriasis by stimulating epidermal keratinocytes to proliferate and to produce cytokines/chemokines and vascular endothelial growth factor (VEGF)-A. Plasmacytoid dendritic cells (pDCs), infiltrating in psoriatic lesions, are known to exacerbate the Th17-mediated pathogenesis of psoriasis.


OBJECTIVE
To address the initiative role of VEGF-A in the development of psoriasis and the pDC accumulation.


METHODS
Numerical changes and VEGF receptor 1 (VEGFR1) and VEGFR2 expressions were investigated in skin-infiltrating T cells and pDCs of K14-VEGF-A transgenic (Tg) and wild type (WT) mice. The chemotactic properties of VEGF-A for purified splenic pDCs were also evaluated by real-time chemotaxis assay.


RESULTS
By flow cytometry and immunohistochemistry, we observed that the number of dermal IL-17A(+) γδ T cells, but not CD4(+) T cells, was increased in VEGF-A Tg mice, suggesting that the main source of IL-17A was γδ T cells. Moreover, we identified pDCs as 440c(+) cells by immunohistochemistry and as PDCA-1(+)B220(+) cells by flow cytometry, and found that pDCs infiltrated at a higher frequency in VEGF-A Tg than WT mice. pDCs, but not γδ T cells, isolated from the skin expressed VEGFR1 and VEGFR2. Freshly isolated splenic pDCs expressed both receptors after 48-h cultivation. pDCs did not produce cytokines in response to VEGF-A, however, they had a strong velocity of chemotaxis toward VEGF-A at a comparable level to chemerin.


CONCLUSIONS
These findings suggest that VEGF-A functions as not only a downstream enhancer but also an upstream initiator by chemoattracting pDCs in psoriatic lesions.
Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Takahiro
T
Suzuki
Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Satoshi
S
Hirakawa
Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Takatoshi
T
Shimauchi
Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Taisuke
T
Ito
Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Jun-ichi
J
Sakabe
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland.
Michael
M
Detmar
Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address: tokura@hama-med.ac.jp.
Yoshiki
Y
Tokura
D000818:Animals; D002630:Chemotactic Factors / Q000378:metabolism; D002633:Chemotaxis; D003713:Dendritic Cells / Q000502:physiology*; D005260:Female; D020381:Interleukin-17 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D039942:Neuropilin-1 / Q000378:metabolism; D011565:Psoriasis / Q000276:immunology* / Q000378:metabolism; D012867:Skin / Q000276:immunology; D058504:Th17 Cells / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D002630:Chemotactic Factors; C098680:Il17a protein, mouse; D020381:Interleukin-17; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D039942:Neuropilin-1; C000592875:Kdr protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2
Chemotaxis; IL-17; Plasmacytoid dendritic cell; Psoriasis; VEGF; γδ T cell