Hyperglycemic Conditions Prime Cells for RIP1-dependent Necroptosis.
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Issue Date
6/24/2016
Authors
LaRocca, Timothy J
Sosunov, Sergey A
Shakerley, Nicole L
Ten, Vadim S
Ratner, Adam J
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Abstract
Necroptosis is a RIP1-dependent programmed cell death (PCD) pathway that is distinct from apoptosis. Downstream effector pathways of necroptosis include formation of advanced glycation end products (AGEs) and reactive oxygen species (ROS), both of which depend on glycolysis. This suggests that increased cellular glucose may prime necroptosis. Here we show that exposure to hyperglycemic levels of glucose enhances necroptosis in primary red blood cells (RBCs), Jurkat T cells, and U937 monocytes. Pharmacologic or siRNA inhibition of RIP1 prevented the enhanced death, confirming it as RIP1-dependent necroptosis. Hyperglycemic enhancement of necroptosis depends upon glycolysis with AGEs and ROS playing a role. Total levels of RIP1, RIP3, and mixed lineage kinase domain-like (MLKL) proteins were increased following treatment with high levels of glucose in Jurkat and U937 cells and was not due to transcriptional regulation. The observed increase in RIP1, RIP3, and MLKL protein levels suggests a potential positive feedback mechanism in nucleated cell types. Enhanced PCD due to hyperglycemia was specific to necroptosis as extrinsic apoptosis was inhibited by exposure to high levels of glucose. Hyperglycemia resulted in increased infarct size in a mouse model of brain hypoxia-ischemia injury. The increased infarct size was prevented by treatment with nec-1s, strongly suggesting that increased necroptosis accounts for exacerbation of this injury in conditions of hyperglycemia. This work reveals that hyperglycemia represents a condition in which cells are extraordinarily susceptible to necroptosis, that local glucose levels alter the balance of PCD pathways, and that clinically relevant outcomes may depend on glucose-mediated effects on PCD.
Citation
LaRocca TJ, Sosunov SA, Shakerley NL, Ten VS, Ratner AJ. Hyperglycemic Conditions Prime Cells for RIP1-dependent Necroptosis. J Biol Chem. 2016 Jun 24;291(26):13753-61. doi: 10.1074/jbc.M116.716027. Epub 2016 Apr 29. PMID: 27129772; PMCID: PMC4919457.
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Grants
R01 AI092743/AI/NIAID NIH HHS/United States , R01 NS088197/NS/NINDS NIH HHS/United States , R21 AI111020/AI/NIAID NIH HHS/United States