Background:Aggravated liver ischemia and reperfusion (IR) injury has been observed in hyperglycemic hosts, but its underlying mechanism remains undefined. The aim of the study was to evaluated the role of endoplasmic reticulum (ER) stress in regulating liver resident macrophages (KCs) activation and liver IR injury in diabetic mice.

Methods: Control (CON) or streptozotocin-induced hyperglycemic/diabetic (STZ) mice were subjected to liver partial IR injury. Liver injury, inflammation and M1/M2 phenotypes of KCs and were evaluated. Signaling pathways of ER stress in stressed KCs were analyzed.

Results: Compared to control group, hyperglycemic mice exhibited a significant increase in liver injury and intrahepatic inflammation following IR. KCs obtained from hyperglycemic mice secreted higher levels of pro-inflammatory TNF-α and IL-6, but significantly lower levels of anti-inflammatory IL-10. Furthermore, enhanced ER stress was revealed by increased C/EBP-Homologous Protein (CHOP) activation in both IR-stressed livers and KCs from hyperglycemic mice. Specific CHOP knockdown in KCs by siRNA resulted in a slight decrease in TNF-α and IL-6 secretion but dramatically enhanced IL-10 secretion in the hyperglycemic group, while no significant changes were observed in the control group. We also analyzed the role of hyperglycemia in macrophage M1/M2 polarization. Interestingly, hyperglycemia inhibited IL-10-secreting M2-like macrophage polarization, as revealed by decreased Arg1 and Mrc1 gene induction accompanied by a decrease in STAT3 and STAT6 signaling pathway activation. CHOP knockdown restored Arg1 and Mrc1 gene induction, STAT3 and STAT6 activation, and most importantly, IL-10 secretion in hyperglycemic KCs. Finally, in vivo CHOP knockdown in KCs enhanced intrahepatic anti-inflammatory IL-10 gene induction and protected the liver against IR injury in hyperglycemic mice but had no significant effects in control mice.

Conclusions: Hyperglycemia-induced CHOP over-activation inhibits IL-10-secreting M2-like macrophage polarization by liver resident macrophages, leading to excessive inflammation and exacerbation of liver IR injury in diabetic/hyperglycemic hosts. This study provides novel mechanistic insight into macrophage inflammatory activation under hyperglycemic conditions during liver IR.

CITATION INFORMATION: Rao Z., Sun J., Pan X., Chen Z., Sun H., Zhang P., Gao M., Ding Z., Liu C. Hyperglycemia Aggravates Hepatic Ischemia and Reperfusion Injury by Inhibiting Liver Resident Macrophage M2 Polarization via C/EBP-Homologous Protein-Mediated Endoplasmic Reticulum Stress Am J Transplant. 2017;17 (suppl 3).

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