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Accumulation of FLT3+ CD11c+ dendritic cells in psoriatic lesions and the anti-psoriatic effect of a selective FLT3 inhibitor

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Abstract

Psoriasis is a common chronic T-cell-mediated autoimmune skin disease, and traditional immunotherapies for psoriasis have focused on the direct inhibition of T cells, which often causes toxicity and lacks long-term effectiveness. Safe and effective therapeutic strategies are strongly needed for psoriasis. In this study, we show for the first time a significant accumulation of FLT3+ CD11c+ dendritic cells (DCs) in human psoriatic lesions and in the skin of experimental preclinical K14-VEGF transgenic homozygous mice, our animal model, although not an exact match for human psoriasis, displays many characteristics of inflammatory skin inflammation. SKLB4771, a potent and selective FLT3 inhibitor that we designed and synthesised, was used to treat cutaneous inflammation and psoriasis-like symptoms of disease in mice and almost completely cured the psoriasis-like disease without obvious toxicity. Mechanistic studies indicated that SKLB4771 treatment significantly decreased the number and activation of pDCs and mDCs in vitro and in vivo, and subsequent T-cell cascade reactions mediated by Th1/Th17 pathways. These findings show that targeted inhibition of FLT3, and hence direct interference with DCs, may be a novel therapeutic approach for the treatment of psoriasis.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (81172987), the National Science and Technology Major Project (2012ZX09501001-003), PCSIRT (IRT13031), and the Applied Basic Research Program of Sichuan Province (2014JY0038). We thank Dr. Tao Chen from the Department of Dermatovenereology, West China Hospital, Sichuan University for his assistance in obtaining patient skin biopsies.

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  1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China

    Heng-Xiu Yan, Wei-Wei Li, Yan Zhang, Xia-Wei Wei, Guo-Bo Shen, Tao Yin, Xiu-Ying Li, Hua-Shan Shi, Yang Wan, Jiong Li, Sheng-Yong Yang & Yu-Quan Wei

  2. College of Life Science and Technology, Southwest University for Nationalities, Chengdu, Sichuan, China

    Heng-Xiu Yan & Li-Xin Fu

  3. Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, China

    Qing-Yin Zhang

  4. Department of Pharmacy, Xijing Hospital, Fourth Military University, Xi’an, China

    Wei-Wei Li

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Correspondence to Sheng-Yong Yang or Yu-Quan Wei.

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Heng-Xiu Yan, Wei-Wei Li and Yan Zhang have contributed equally to this work.

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12026_2014_8521_MOESM1_ESM.tif

Supplement Fig 1 Inhibition of FLT3 + CD11c + precursor in bone marrow by SKLB4771 treatment in vivo. Flow cytometric quantification of FLT3+ CD11c+ precursor in bone marrow isolated from vehicle-treated psoriatic plaque lesions and SKLB4771-treated lesions. The number of decreased in psoriatic plaque lesions of SKLB4771-treated mice when compared with vehicle-treated mice (mean ± S.D., n = 6 per group). Ordinates in the histogram indicate the percentage of FLT3+ CD11c+ precursor within total cells. Data are representative of three independent experiments. (TIFF 80 kb)

12026_2014_8521_MOESM2_ESM.tif

Supplement Fig 2 Inhibition of IL-12p70 by SKLB4771 treatment in vivo. Homogenised ear tissues from SKLB4771- or vehicle-treated groups were investigated by ELISA. The amount of IL-12p70 was found to be significantly decreased in SKLB4771-treated mice (mean ± S.D., n = 3 per group). (TIFF 232 kb)

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Yan, HX., Li, WW., Zhang, Y. et al. Accumulation of FLT3+ CD11c+ dendritic cells in psoriatic lesions and the anti-psoriatic effect of a selective FLT3 inhibitor. Immunol Res 60, 112–126 (2014). https://doi.org/10.1007/s12026-014-8521-4

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