title: Accumulation of FLT3(+) CD11c (+) dendritic cells in psoriatic lesions and the anti-psoriatic effect of a selective FLT3 inhibitor.
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.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Heng-Xiu
authors.initials: HX
authors.lastname: Yan
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xia-Wei
authors.initials: XW
authors.lastname: Wei
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Fu
authors.forename: Guo-Bo
authors.initials: GB
authors.lastname: Shen
authors.forename: Tao
authors.initials: T
authors.lastname: Yin
authors.forename: Xiu-Ying
authors.initials: XY
authors.lastname: Li
authors.forename: Hua-Shan
authors.initials: HS
authors.lastname: Shi
authors.forename: Yang
authors.initials: Y
authors.lastname: Wan
authors.forename: Qing-Yin
authors.initials: QY
authors.lastname: Zhang
authors.forename: Jiong
authors.initials: J
authors.lastname: Li
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Wei
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D039521:CD11c Antigen / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D003872:Dermatitis / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D053547:Keratin-14 / Q000235:genetics; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011565:Psoriasis / Q000188:drug therapy / Q000276:immunology*; D013830:Thiadiazoles / Q000494:pharmacology / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: C573559:1-(5-(7-(3-morpholinopropoxy)quinazolin-4-ylthio)-(1,3,4)thiadiazol-2-yl)-3-p-tolylurea; D000893:Anti-Inflammatory Agents; D039521:CD11c Antigen; D053547:Keratin-14; C507446:Krt14 protein, mouse; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D013830:Thiadiazoles; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3