Deletion of the microbially regulated enzyme hexokinase 2 in intestinal epithelial cells protects from intestinal inflammation and cell death

Upregulation of glycolytic enzymes as well as glycolysis in general has been observed in a plethora of immune cells and some non-immunological cells. In our study, we show upregulation of the glycolytic pace-maker enzyme Hexokinase 2 (HK2) in intestinal epithelial cells (IECs) upon intestinal inflammation and inflammatory bowel disease (IBD). In accordance with this observation, deletion of Hk2 in IECs specifically conferred protection upon acute colitis. Moreover, deletion of Hk2 in IECs did not entail any negative consequences regarding whole body glucose homeostasis or glycolytic function in IECs suggesting IEC-specific ablation of Hk2 as safe. Functionally, we show that the mechanism of how loss of Hk2 ameliorates inflammation is not attributed to a role in glycolysis. Instead, our study provides evidence that loss of Hk2 leads to reduced intestinal epithelial cell death. We propose that mechanistically, this effect is facilitated by downregulation of Peptidyl-prolyl cis-trans isomerase(Ppif) which is critically involved in mitochondria-mediated cell death via the mitochondrial permeability transition pore (mPTP). In line with this we observed a lower mitochondrial membrane permeability and reduced markers of mitochondria-mediated cell death following deletion of Hk2 in IECs. We therefore propose HK2 as a novel target for IBD and intestinal inflammation in general.

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