Acetylation-Dependent Regulation of Notch Signaling in Macrophages by SIRT1 Affects Sepsis Development.
Acetylation-Dependent Regulation of Notch Signaling in Macrophages by SIRT1 Affects Sepsis Development.
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SIRT1 对巨噬细胞中 Notch 信号传导的乙酰化依赖性调节影响脓毒症的发展
DOI：
10.3389/fimmu.2018.00762
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发表时间：
2018
影响因子：
7.3
通讯作者：
Hu D
中科院分区：
文献类型：
--
作者：
Bai X;He T;Liu Y;Zhang J;Li X;Shi J;Wang K;Han F;Zhang W;Zhang Y;Cai W;Hu D
据报道，SIRT1参与巨噬细胞分化并影响脓毒症，同时Notch信号通路被广泛报道可影响炎症和巨噬细胞活化。然而，SIRT1调节脓毒症的具体机制以及SIRT1和Notch信号通路之间的关系仍未得到充分阐明。在本研究中，我们发现体内外脓毒症中SIRT1水平均降低，且SIRT1对Notch信号通路的调节影响炎症。在脂多糖（LPS）诱导的脓毒症中，Notch信号分子水平，包括Notch1、Notch2、Hes1和Notch胞内段（NICD）均升高。然而，NICD可被SIRT1去乙酰化，这导致Notch信号通路受到抑制。值得注意的是，在髓系特异性RBP - J−/−小鼠的巨噬细胞中（其中Notch信号通路被抑制），促炎细胞因子的表达水平低于野生型同窝小鼠的巨噬细胞，并且在RBP - J−/−巨噬细胞中，NF - κB通路也被抑制。相应地，在RBP - J−/−小鼠中，LPS诱导的炎症和死亡率低于野生型小鼠。我们的研究结果表明，SIRT1通过NICD去乙酰化抑制Notch信号通路，从而最终缓解脓毒症。
SIRT1 is reported to participate in macrophage differentiation and affect sepsis, and Notch signaling is widely reported to influence inflammation and macrophage activation. However, the specific mechanisms through which SIRT1 regulates sepsis and the relationship between SIRT1 and Notch signaling remain poorly elucidated. In this study, we found that SIRT1 levels were decreased in sepsis both in vitro and in vivo and that SIRT1 regulation of Notch signaling affected inflammation. In lipopolysaccharide (LPS)-induced sepsis, the levels of Notch signaling molecules, including Notch1, Notch2, Hes1, and intracellular domain of Notch (NICD), were increased. However, NICD could be deacetylated by SIRT1, and this led to the suppression of Notch signaling. Notably, in macrophages from myeloid-specific RBP-J−/− mice, in which Notch signaling is inhibited, pro-inflammatory cytokines were expressed at lower levels than in macrophages from wild-type littermates and in RBP-J−/− macrophages, and the NF-κB pathway was also inhibited. Accordingly, in the case of RBP-J−/− mice, LPS-induced inflammation and mortality were lower than in wild-type mice. Our results indicate that SIRT1 inhibits Notch signaling through NICD deacetylation and thus ultimately alleviates sepsis.
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影响因子：
64.8
作者：
Guarani V;Deflorian G;Franco CA;Krüger M;Phng LK;Bentley K;Toussaint L;Dequiedt F;Mostoslavsky R;Schmidt MHH;Zimmermann B;Brandes RP;Mione M;Westphal CH;Braun T;Zeiher AM;Gerhardt H;Dimmeler S;Potente M
通讯作者：
Potente M
通过 RBP-J 敲除对 Notch 信号传导进行骨髓特异性阻断可减轻小鼠脊髓损伤并伴有炎症反应受损
影响因子：
5.1
作者：
Chen, Bei-Yu;Zheng, Min-Hua;Han, Hua
通讯作者：
Han, Hua
影响因子：
6.7
作者：
Liu, Rui;Pan, Xiaomin;Whitington, Peter F.
通讯作者：
Whitington, Peter F.
影响因子：
11.2
作者：
Ban, Jozef;Aryee, Dave N. T.;Kovar, Heinrich
通讯作者：
Kovar, Heinrich
影响因子：
11.4
作者：
Kim, Dohoon;Nguyen, Minh Dang;Tsai, Li-Huei
通讯作者：
Tsai, Li-Huei