3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation.
3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation.
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DOI：
10.1038/srep42412
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发表时间：
2017-02-10
影响因子：
4.6
通讯作者：
Morinobu A
中科院分区：
文献类型：
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作者：
Okano T;Saegusa J;Nishimura K;Takahashi S;Sendo S;Ueda Y;Morinobu A
最近的研究表明，细胞代谢在调节免疫细胞功能中发挥着重要作用。在免疫细胞分化中，产生白细胞介素 17 的 T (Th17) 细胞和树突状细胞 (DC) 通过上调糖酵解酶（如己糖激酶 2 (HK2)）表现出糖酵解增强。最近显示，用 2-脱氧葡萄糖阻断糖酵解可以抑制 Th17 细胞分化，同时促进调节性 T (Treg) 细胞生成。然而，2-DG 抑制 HK 的所有亚型。因此，尚不清楚哪种亚型在 Th17 细胞分化和类风湿性关节炎 (RA) 发病机制中起关键作用。在这里，我们证明了特异性 HK2 抑制剂 3-溴丙酮酸 (BrPA) 显着降低了 SKG 小鼠的关节炎评分和组织学评分，脾脏中 Treg 细胞显着增加，Th17 细胞减少，活化 DC 减少。在体外，BrPA促进Treg细胞的分化，抑制Th17细胞，并抑制DC的活化。这些结果表明 BrPA 可能是小鼠关节炎的治疗靶点。尽管IL-17在RA治疗中的作用尚未明确，但靶向细胞代谢来改变免疫细胞功能可能会为RA带来新的治疗策略。
Recent studies have shown that cellular metabolism plays an important role in regulating immune cell functions. In immune cell differentiation, both interleukin-17-producing T (Th17) cells and dendritic cells (DCs) exhibit increased glycolysis through the upregulation of glycolytic enzymes, such as hexokinase-2 (HK2). Blocking glycolysis with 2-deoxyglucose was recently shown to inhibit Th17 cell differentiation while promoting regulatory T (Treg) cell generation. However, 2-DG inhibits all isoforms of HK. Thus, it is unclear which isoform has a critical role in Th17 cell differentiation and in rheumatoid arthritis (RA) pathogenesis. Here we demonstrated that 3-bromopyruvate (BrPA), a specific HK2 inhibitor, significantly decreased the arthritis scores and the histological scores in SKG mice, with a significant increase in Treg cells, decrease in Th17 cells, and decrease in activated DCs in the spleen. In vitro, BrPA facilitated the differentiation of Treg cells, suppressed Th17 cells, and inhibited the activation of DCs. These results suggested that BrPA may be a therapeutic target of murine arthritis. Although the role of IL-17 is not clarified in the treatment of RA, targeting cell metabolism to alter the immune cell functions might lead to a new therapeutic strategy for RA.