title: Knockout of P2Y12aggravates experimental autoimmune encephalomyelitis in mice via increasing of IL-23 production and Th17 cell differentiation by dendritic cells.
abstract: Experimental autoimmune encephalomyelitis (EAE), a common model of multiple sclerosis (MS), is mainly mediated by CD4+T cells with demyelination and neurodegeneration of central nervous system (CNS). The loss of P2Y12receptor might be associated with the pathogenesis of MS/EAE, but its potential mechanism is still not clear. In this study, more severe EAE developed in P2Y12-knockout (P2Y12-KO) mice compared to WT mice. Knockout of P2Y12increased expression of IL-17A in the sera and proportion of Th17 cells in spleen and CNS. However, in vitro studies showed that P2Y12did not influence cell differentiation and proliferation of CD4+T cells. In bone marrow-derived dendritic cells (BMDCs), loss of P2Y12significantly increased the production of IL-23 in contrast to the wild-type (WT) BMDCs. FACS analysis indicated that the culture supernatant from P2Y12-deficient DCs promoted more naïve CD4+ T cells to differentiate into Th17 cells. Our finding demonstrated that genetic deletion of P2Y12receptor broke the balance of Th subtypes by affecting the cytokine profile of BMDCs and resulted in the aggravated EAE, which suggested that P2Y12may be a potential target in treating MS.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Zhenlong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Hu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Su
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Cong
authors.initials: C
authors.lastname: He
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Ren
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Qian
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Junling
authors.initials: J
authors.lastname: Liu
authors.affiliation: Laboratory Animal Center, Second Military Medical University, Shanghai, China. Electronic address: youngstar_sf@163.com.
authors.forename: Shufang
authors.initials: S
authors.lastname: Cui
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China. Electronic address: wzjiang@bio.ecnu.edu.cn.
authors.forename: Wenzheng
authors.initials: W
authors.lastname: Jiang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D003713:Dendritic Cells / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D058925:Receptors, Purinergic P2Y12 / Q000235:genetics / Q000378:metabolism*; D058504:Th17 Cells / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; D053759:Interleukin-23; C548577:P2ry12 protein, mouse; D058925:Receptors, Purinergic P2Y12
keywords: DC; EAE; IL-23; Knockout; P2Y(12); Th17