TNFα 和 IFNγ 快速激活 PI3K-AKT 信号传导以驱动糖酵解，从而赋予间充质干细胞增强的抗炎特性,Stem Cell Research & Therapy

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TNFα 和 IFNγ 快速激活 PI3K-AKT 信号传导以驱动糖酵解，从而赋予间充质干细胞增强的抗炎特性
Stem Cell Research & Therapy ( IF 7.1 ) Pub Date : 2022-10-04 , DOI: 10.1186/s13287-022-03178-3
Chenchang Xu _{1,

2} , Chao Feng ₁ , Peiqing Huang ₁ , Yinghong Li ₁ , Rui Liu ₁ , Chunxiao Liu ₁ , Yuyi Han ₁ , Lei Chen ₂ , Yayun Ding ₁ , Changshun Shao ₁ , Yufang Shi ₁

Affiliation

间充质干/基质细胞 (MSCs) 仅在炎症微环境中获得免疫抑制能力。这可以在体外通过用炎性细胞因子 TNFα 和 IFNγ 处理 MSCs 来概括，这会诱导吲哚胺 2,3-双加氧酶 (IDO) 和 TNF 刺激的基因 6 (TSG-6)。然而，细胞因子下游的信号通路仍有待阐明。炎症性肠病 (IBD) 小鼠模型是通过使小鼠在饮用水中接受葡聚糖硫酸钠 (DSS) 7 天来建立的。人 UC-MSCs 用 TNF-α 和 IFN-γ 预处理 24 小时，然后在 DSS 给药的第 2 天静脉内输注。收集结肠组织用于长度测量和组织病理学检查。采用酶联免疫吸附法测定小鼠血清IL-6水平。实时荧光定量 PCR 和蛋白质印迹用于检查 mRNA 水平和蛋白质表达。产生并分析过表达组成型活性AKT或显性失活AKT的MSC。使用细胞外通量分析仪测量 MSCs 的糖酵解水平。2-NBDG 用于监测 MSCs 对葡萄糖的摄取。TNFα 和 IFNγ 治疗导致 MSCs 中葡萄糖的快速消耗和代谢偏向糖酵解，这是 MSCs 对 IBD 的治疗效果所必需的。阻断间充质干细胞中的糖酵解可抑制免疫调节分子 IDO 和 TSG-6 的表达，以及对 IBD 的治疗作用。此外，PI3K-AKT 信号轴被迅速激活，并且是 TNFα 和 IFNγ 诱导的糖酵解倾斜所必需的。表达显性阴性 AKT 的 MSCs 对 IBD 的治疗效果受到损害。炎症细胞因子赋予间充质干细胞糖酵解依赖性抗炎特性是由PI3K-AKT信号通路介导的。

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TNFα and IFNγ rapidly activate PI3K-AKT signaling to drive glycolysis that confers mesenchymal stem cells enhanced anti-inflammatory property

Mesenchymal stem/stromal cells (MSCs) acquire immunosuppressive capacity only in an inflammatory microenvironment. This can be recapitulated in vitro by treating MSCs with inflammatory cytokines TNFα and IFNγ, which induce indoleamine 2,3-dioxygenase (IDO) and TNF-stimulated gene-6 (TSG-6). However, the signaling pathways downstream of the cytokines remain to be elucidated. Inflammatory bowel disease (IBD) mouse model was established by subjecting mice to dextran sulfate sodium (DSS) in drinking water for 7 days. Human UC-MSCs were pretreated with TNF-α and IFN-γ for 24 h and were then infused intravenously at day 2 of DSS administration. Colon tissues were collected for length measurement and histopathological examination. The serum level of IL-6 in mice was measured by enzyme-linked immunosorbent assay. Real-time PCR and Western blot were used to examine the mRNA level and protein expression. MSCs overexpressing constitutive active AKT or dominant negative AKT were generated and were analyzed. The glycolysis level of the MSCs was measured using Extracellular Flux Analyzer. 2-NBDG was used to monitor the uptake of glucose by MSCs. TNFα and IFNγ treatment led to rapid consumption of glucose and metabolic skewing toward glycolysis in MSCs, which was required for the therapeutic efficacy of MSCs on IBD. Blockade of glycolysis in MSCs inhibited the expression of immunomodulatory molecules, IDO and TSG-6, as well as the therapeutic effect on IBD. Moreover, PI3K-AKT signaling axis was rapidly activated and was required for the skewing toward glycolysis induced by TNFα and IFNγ. MSCs expressing dominant negative AKT were compromised in their therapeutic efficacy on IBD. The glycolysis-dependent anti-inflammatory property of MSCs conferred by inflammatory cytokines is mediated by PI3K-AKT signaling pathway.

更新日期：2022-10-04

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