Hyperglycemia potentiates a shift from apoptosis to RIP1-dependent necroptosis.
Hyperglycemia potentiates a shift from apoptosis to RIP1-dependent necroptosis.
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DOI：
10.1038/s41420-018-0058-1
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发表时间：
2018
影响因子：
7
通讯作者：
LaRocca TJ
中科院分区：
文献类型：
--
作者：
McCaig WD;Patel PS;Sosunov SA;Shakerley NL;Smiraglia TA;Craft MM;Walker KM;Deragon MA;Ten VS;LaRocca TJ
凋亡和坏死性凋亡是真核细胞死亡的主要模式，其中凋亡是非炎症性的，而坏死性凋亡是高度炎症性的。我们之前证明，一旦激活，几种细胞类型中的高血糖会增强坏死性凋亡。在这里，我们确定高血糖是否同样影响细胞凋亡。我们发现，高血糖并不增强外源性细胞凋亡，但增强了RIP 1依赖性坏死性凋亡的转变。这是由于在高血糖条件下刺激细胞凋亡后，RIP 1、RIP 3和MLKL的水平和活性增加，以及执行者半胱天冬酶的水平和活性降低。通过测量标志物和RIP 1、RIP 3和MLKL的参与，将高血糖条件下的细胞死亡分类为坏死性凋亡。向坏死性凋亡的转变是由RIP 1驱动的，因为使用CRISPR-Cas9的该基因突变导致细胞死亡在高血糖条件下恢复为凋亡。细胞凋亡向坏死性凋亡的转变依赖于糖酵解和线粒体ROS的产生。重要的是，在原代人T细胞中观察到PCD的转变。RIP 1和MLKL的水平增加，而刽子手半胱天冬酶和PARP 1裂解减少，在高血糖新生小鼠，经历缺氧缺血（HI）脑损伤的脑组织中，表明这种细胞死亡转移发生在体内。这是重要的，因为它证明了从非炎性细胞死亡到炎性细胞死亡的转变，这可以解释高血糖症期间新生儿HI脑损伤的恶化。这些结果与我们以前的研究结果不同，其中高血糖在人工抑制细胞凋亡的条件下增强坏死性凋亡。在这里，我们证明了从细胞凋亡的转变，坏死性凋亡在高血糖条件下，而这两个途径是完全活跃的。因此，虽然我们以前的工作证明了坏死性凋亡的强度对葡萄糖有反应，但这项工作揭示了细胞凋亡和坏死性凋亡之间的分子平衡，并将高血糖症确定为一种推动细胞发生坏死性凋亡的条件，尽管细胞凋亡最初被激活。
Apoptosis and necroptosis are the primary modes of eukaryotic cell death, with apoptosis being non-inflammatory while necroptosis is highly inflammatory. We previously demonstrated that, once activated, necroptosis is enhanced by hyperglycemia in several cell types. Here, we determine if hyperglycemia affects apoptosis similarly. We show that hyperglycemia does not enhance extrinsic apoptosis but potentiates a shift to RIP1-dependent necroptosis. This is due to increased levels and activity of RIP1, RIP3, and MLKL, as well as decreased levels and activity of executioner caspases under hyperglycemic conditions following stimulation of apoptosis. Cell death under hyperglycemic conditions was classified as necroptosis via measurement of markers and involvement of RIP1, RIP3, and MLKL. The shift to necroptosis was driven by RIP1, as mutation of this gene using CRISPR–Cas9 caused cell death to revert to apoptosis under hyperglycemic conditions. The shift of apoptosis to necroptosis depended on glycolysis and production of mitochondrial ROS. Importantly, the shift in PCD was observed in primary human T cells. Levels of RIP1 and MLKL increased, while executioner caspases and PARP1 cleavage decreased, in cerebral tissue from hyperglycemic neonatal mice that underwent hypoxia-ischemia (HI) brain injury, suggesting that this cell death shift occurs in vivo. This is significant as it demonstrates a shift from non-inflammatory to inflammatory cell death which may explain the exacerbation of neonatal HI-brain injury during hyperglycemia. These results are distinct from our previous findings where hyperglycemia enhanced necroptosis under conditions where apoptosis was inhibited artificially. Here we demonstrate a shift from apoptosis to necroptosis under hyperglycemic conditions while both pathways are fully active. Therefore, while our previous work documented that intensity of necroptosis is responsive to glucose, this work sheds light on the molecular balance between apoptosis and necroptosis and identifies hyperglycemia as a condition that pushes cells to undergo necroptosis despite the initial activation of apoptosis.
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DOI：
10.1186/1478-811x-8-31
发表时间：
2010-12-22
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Chaitanya GV;Steven AJ;Babu PP
通讯作者：
Babu PP
影响因子：
8.8
作者：
Palchaudhuri R;Lambrecht MJ;Botham RC;Partlow KC;van Ham TJ;Putt KS;Nguyen LT;Kim SH;Peterson RT;Fan TM;Hergenrother PJ
通讯作者：
Hergenrother PJ
影响因子：
5
作者：
Stefano GB;Challenger S;Kream RM
通讯作者：
Kream RM
影响因子：
4.3
作者：
Allaman I;Bélanger M;Magistretti PJ
通讯作者：
Magistretti PJ
DOI：
10.4161/derm.22028
发表时间：
2012-07-01
期刊：
Dermato-endocrinology
影响因子：
--
作者：
Gkogkolou P;Böhm M
通讯作者：
Böhm M