Taurine Antagonizes Macrophages M1 Polarization by Mitophagy-Glycolysis Switch Blockage via Dragging SAM-PP2Ac Transmethylation.
Taurine Antagonizes Macrophages M1 Polarization by Mitophagy-Glycolysis Switch Blockage via Dragging SAM-PP2Ac Transmethylation.
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牛磺酸通过拖动 SAM-PP2Ac 转甲基化阻断线粒体自噬-糖酵解开关来拮抗巨噬细胞 M1 极化
DOI：
10.3389/fimmu.2021.648913
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发表时间：
2021
影响因子：
7.3
通讯作者：
Tang S
中科院分区：
文献类型：
--
作者：
Meng L;Lu C;Wu B;Lan C;Mo L;Chen C;Wang X;Zhang N;Lan L;Wang Q;Zeng X;Li X;Tang S
巨噬细胞的M1极化过度驱动炎症性疾病的发生和发展。通过靶向代谢事件可实现巨噬细胞从M1向M2的重编程。牛磺酸促进能量代谢平衡和炎症损伤修复，预防慢性疾病及其并发症。然而，对于牛磺酸调节巨噬细胞极化表型的作用机制知之甚少。在本研究中，我们构建了低剂量脂多糖/干扰素 -γ诱导的M1极化模型以模拟低度促炎过程。我们的结果表明，在M1巨噬细胞极化过程中，牛磺酸转运体TauT/SlC6A6在转录水平上调。膜上的营养摄取信号支持补充牛磺酸后巨噬细胞中牛磺酸的高含量，这削弱了蛋氨酸代谢状态，导致S -腺苷甲硫氨酸（SAM）不足。LCMT - 1和PME - 1直接感知到SAM的低可用性，阻碍PP2Ac甲基化。发现PP2Ac甲基化对于M1极化是必需的，包括对VDAC1和PINK1的正向调节。此外，发现其激活可促进巨噬细胞通过线粒体自噬途径清除线粒体以实现代谢适应。从机制上讲，牛磺酸抑制SAM依赖的PP2Ac甲基化以阻断PINK1介导的线粒体自噬通量，从而维持较高的线粒体密度，最终阻碍M1所需的能量代谢向糖酵解的转变。我们的研究结果揭示了牛磺酸耦合M1巨噬细胞能量代谢的一种新机制，为低度炎症的发生和预防提供了新的见解，并提出牛磺酸和SAM可用性的感知可能使巨噬细胞与炎症反应相互联系。
The excessive M1 polarization of macrophages drives the occurrence and development of inflammatory diseases. The reprogramming of macrophages from M1 to M2 can be achieved by targeting metabolic events. Taurine promotes for the balance of energy metabolism and the repair of inflammatory injury, preventing chronic diseases and complications. However, little is known about the mechanisms underlying the action of taurine modulating the macrophage polarization phenotype. In this study, we constructed a low-dose LPS/IFN-γ-induced M1 polarization model to simulate a low-grade pro-inflammatory process. Our results indicate that the taurine transporter TauT/SlC6A6 is upregulated at the transcriptional level during M1 macrophage polarization. The nutrient uptake signal on the membrane supports the high abundance of taurine in macrophages after taurine supplementation, which weakens the status of methionine metabolism, resulting in insufficient S-adenosylmethionine (SAM). The low availability of SAM is directly sensed by LCMT-1 and PME-1, hindering PP2Ac methylation. PP2Ac methylation was found to be necessary for M1 polarization, including the positive regulation of VDAC1 and PINK1. Furthermore, its activation was found to promote the elimination of mitochondria by macrophages via the mitophagy pathway for metabolic adaptation. Mechanistically, taurine inhibits SAM-dependent PP2Ac methylation to block PINK1-mediated mitophagy flux, thereby maintaining a high mitochondrial density, which ultimately hinders the conversion of energy metabolism to glycolysis required for M1. Our findings reveal a novel mechanism of taurine-coupled M1 macrophage energy metabolism, providing novel insights into the occurrence and prevention of low-grade inflammation, and propose that the sensing of taurine and SAM availability may allow communication to inflammatory response in macrophages.
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DOI：
10.1038/nri.2016.100
发表时间：
2016-11
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
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通讯作者：
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DOI：
10.1073/pnas.1712465114
发表时间：
2017-11-07
影响因子：
11.1
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影响因子：
5.2
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DOI：
10.1073/pnas.1014156108
发表时间：
2011-01-25
影响因子：
11.1
作者：
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DOI：
10.1073/pnas.1015248108
发表时间：
2011-04-26
影响因子：
11.1
作者：
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