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(+) gamma delta T cells, but not CD4(+) T cells, was increased in VEGF-A Tg mice, suggesting that the main source of IL-17A was gamma delta 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 gamma delta 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. (C) 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.