Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE.
Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE.
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DOI：
10.1371/journal.pone.0007897
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发表时间：
2009-11-19
期刊：
影响因子：
3.7
通讯作者：
Nencioni A
中科院分区：
文献类型：
--
作者：
Bruzzone S;Fruscione F;Morando S;Ferrando T;Poggi A;Garuti A;D'Urso A;Selmo M;Benvenuto F;Cea M;Zoppoli G;Moran E;Soncini D;Ballestrero A;Sordat B;Patrone F;Mostoslavsky R;Uccelli A;Nencioni A
烟酰胺磷酸核糖基转移酶（Nampt）抑制剂，如FK866，是NAD+合成的有效抑制剂，有望用于治疗不同形式的癌症。基于活化T淋巴细胞Nampt的上调和FK866治疗患者淋巴细胞减少的初步报告，我们研究了FK866对T淋巴细胞功能和存活的干扰能力。在静止和活化的人T淋巴细胞中评估细胞内吡啶核苷酸、ATP、线粒体功能、活力、增殖、激活标志物和细胞因子分泌。此外，我们使用实验性自身免疫性脑脊髓炎（EAE）作为t细胞介导的自身免疫性疾病模型来评估FK866在体内的疗效。我们发现激活而非静止的T淋巴细胞在fk866介导的Nampt抑制下发生大量NAD+消耗。因此，增殖受损，IFN-γ和TNF-α产生减少，最终导致细胞自噬死亡。我们证明，活化的T细胞上调NAD+降解酶聚（adp -核糖）聚合酶（PARP）可增强其对NAD+耗损的易感性。此外，我们将FK866对IFN-γ和TNF-α产生缺陷的反应与Sirt6活性受损联系起来。最后，我们发现FK866显著减轻了EAE的神经损伤和临床表现。总之，Nampt抑制剂（可能还有Sirt6抑制剂）可用于调节T细胞介导的免疫反应，从而对免疫介导的疾病有益。
Nicotinamide phosphoribosyltransferase (Nampt) inhibitors such as FK866 are potent inhibitors of NAD+ synthesis that show promise for the treatment of different forms of cancer. Based on Nampt upregulation in activated T lymphocytes and on preliminary reports of lymphopenia in FK866 treated patients, we have investigated FK866 for its capacity to interfere with T lymphocyte function and survival. Intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers and cytokine secretion were assessed in resting and in activated human T lymphocytes. In addition, we used experimental autoimmune encephalomyelitis (EAE) as a model of T-cell mediated autoimmune disease to assess FK866 efficacy in vivo. We show that activated, but not resting, T lymphocytes undergo massive NAD+ depletion upon FK866-mediated Nampt inhibition. As a consequence, impaired proliferation, reduced IFN-γ and TNF-α production, and finally autophagic cell demise result. We demonstrate that upregulation of the NAD+-degrading enzyme poly-(ADP-ribose)-polymerase (PARP) by activated T cells enhances their susceptibility to NAD+ depletion. In addition, we relate defective IFN-γ and TNF-α production in response to FK866 to impaired Sirt6 activity. Finally, we show that FK866 strikingly reduces the neurological damage and the clinical manifestations of EAE. In conclusion, Nampt inhibitors (and possibly Sirt6 inhibitors) could be used to modulate T cell-mediated immune responses and thereby be beneficial in immune-mediated disorders.
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影响因子：
4.8
作者：
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通讯作者：
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