Midkine Inhibits Inducible Regulatory T Cell Differentiation by Suppressing the Development of Tolerogenic Dendritic Cells
Midkine Inhibits Inducible Regulatory T Cell Differentiation by Suppressing the Development of Tolerogenic Dendritic Cells
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DOI：
10.4049/jimmunol.1102346
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发表时间：
2012-03-15
影响因子：
4.4
通讯作者：
Suzumura, Akio
中科院分区：
文献类型：
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作者：
Sonobe, Yoshifumi;Li, Hua;Suzumura, Akio
中期因子(Midkine，MK)是一种肝素结合生长因子，据报道，它与包括克罗恩病和类风湿性关节炎在内的炎症性疾病有关。我们以前发现，MK通过减少调节性CD4(+)CD25(+)Foxp3(+)T细胞(Tregs)来加重实验性自身免疫性脑脊髓炎(EAE)，Tregs是一种调节自身免疫反应发展的群体，尽管确切的机制尚不清楚。在这篇文章中，我们证明在炎症条件下产生的MK抑制耐受性树突状细胞(DCregs)的发展，DCregs驱动诱导性Treg的发展。MK抑制DCreg介导的CD4(+)CD25(+)Foxp3(+)Treg群体的扩张。与常规树突状细胞相比，DCregs表达CD45RB的水平显著升高，产生的IL-12显著减少。然而，MK通过在DCreg中通过src同源区2结构域含磷酸酶-2降低磷酸化的STAT3水平，下调CD45Rb的表达，并诱导IL-12的产生。用与靶蛋白结合以抑制蛋白功能的抗MK RNA适体抑制MK活性，增加引流淋巴结中CD11c(低)CD45Rb(+)树突状细胞和Treg的数量，并抑制多发性硬化症动物模型EAE的严重程度。我们的结果还表明，在炎症条件下，MK是由炎症细胞产生的，尤其是CD4(+)T细胞。综上所述，这些结果表明，MK通过抑制DCreg的发育而加重EAE，从而损害Treg群体。因此，MK是治疗各种自身免疫性疾病的有前景的靶点。免疫学杂志，2012,188：2602-2611。
Midkine (MK), a heparin-binding growth factor, reportedly contributes to inflammatory diseases, including Crohn's disease and rheumatoid arthritis. We previously showed that MK aggravates experimental autoimmune encephalomyelitis (EAE) by decreasing regulatory CD4(+)CD25(+)Foxp3(+) T cells (Tregs), a population that regulates the development of autoimmune responses, although the precise mechanism remains uncertain. In this article, we show that MK produced in inflammatory conditions suppresses the development of tolerogenic dendritic cells (DCregs), which drive the development of inducible Treg. MK suppressed DCreg-mediated expansion of the CD4(+)CD25(+)Foxp3(+) Treg population. DCregs expressed significantly higher levels of CD45RB and produced significantly less IL-12 compared with conventional dendritic cells. However, MK downregulated CD45RB expression and induced IL-12 production by reducing phosphorylated STAT3 levels via src homology region 2 domain-containing phosphatase-2 in DCreg. Inhibiting MK activity with anti-MK RNA aptamers, which bind to the targeted protein to suppress the function of the protein, increased the numbers of CD11c(low)CD45RB(+) dendritic cells and Tregs in the draining lymph nodes and suppressed the severity of EAE, an animal model of multiple sclerosis. Our results also demonstrated that MK was produced by inflammatory cells, in particular, CD4(+) T cells under inflammatory conditions. Taken together, these results suggest that MK aggravates EAE by suppressing DCreg development, thereby impairing the Treg population. Thus, MK is a promising therapeutic target for various autoimmune diseases. The Journal of Immunology, 2012, 188: 2602-2611.