Myeloid Deletion of SIRT1 Induces Inflammatory Signaling in Response to Environmental Stress
Myeloid Deletion of SIRT1 Induces Inflammatory Signaling in Response to Environmental Stress
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DOI：
10.1128/mcb.00657-10
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发表时间：
2010-10-01
影响因子：
5.3
通讯作者：
Li, Xiaoling
中科院分区：
文献类型：
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作者：
Schug, Thaddeus T.;Xu, Qing;Li, Xiaoling
已知巨噬细胞活化和浸润到驻留组织中介导局部炎症，并且是代谢综合征的标志性特征。沉默调节蛋白家族的成员调节许多生理过程，包括参与营养调节和促进长寿的过程。然而，SIRT 1，主要的sirtuin家族成员，在免疫应答中发挥的重要作用仍不清楚。在这项研究中，我们证明SIRT 1调节NF-κ B B的RelA/p65亚基的乙酰化状态，从而在调节哺乳动物的炎症，免疫和凋亡反应中发挥关键作用。使用骨髓细胞特异性SIRT 1敲除（Mac-SIRT 1 KO）小鼠模型，我们发现，在巨噬细胞中SIRT 1的消融使NF-κ B B过度乙酰化，导致促炎靶基因的转录激活增加。与促炎基因表达增加一致，用高脂饮食激发的Mac-SIRT 1 KO小鼠在肝脏和脂肪组织中显示高水平的活化巨噬细胞，使动物易于发展全身性胰岛素抵抗和代谢紊乱。总之，我们报道了SIRT 1在巨噬细胞中的作用是抑制NF-κ B介导的转录，这意味着骨髓细胞特异性调节这种sirtuin可能有益于炎症及其相关疾病的治疗。
Macrophage activation and infiltration into resident tissues is known to mediate local inflammation and is a hallmark feature of metabolic syndrome. Members of the sirtuin family of proteins regulate numerous physiological processes, including those involved in nutrient regulation and the promotion of longevity. However, the important role that SIRT1, the leading sirtuin family member, plays in immune response remains unclear. In this study, we demonstrate that SIRT1 modulates the acetylation status of the RelA/p65 subunit of NF-kappa B and thus plays a pivotal role in regulating the inflammatory, immune, and apoptotic responses in mammals. Using a myeloid cell-specific SIRT1 knockout (Mac-SIRT1 KO) mouse model, we show that ablation of SIRT1 in macrophages renders NF-kappa B hyperacetylated, resulting in increased transcriptional activation of proinflammatory target genes. Consistent with increased proinflammatory gene expression, Mac-SIRT1 KO mice challenged with a high-fat diet display high levels of activated macrophages in liver and adipose tissue, predisposing the animals to development of systemic insulin resistance and metabolic derangement. In summary, we report that SIRT1, in macrophages, functions to inhibit NF-kappa B-mediated transcription, implying that myeloid cell-specific modulation of this sirtuin may be beneficial in the treatment of inflammation and its associated diseases.