Hyperglycemia Aggravates Hepatic Ischemia and Reperfusion Injury by Inhibiting Liver-Resident Macrophage M2 Polarization via C/EBP Homologous Protein-Mediated Endoplasmic Reticulum Stress

Abstract

Aggravated liver ischemia and reperfusion (IR) injury has been observed in hyperglycemic hosts, but its underlying mechanism remains undefined. Liver-resident macrophages (Kupffer cells, KCs) and endoplasmic reticulum (ER) stress play crucial roles in the pathogenesis of liver IR injury. In this study, we evaluated the role of ER stress in regulating KC activation and liver IR injury in a streptozotocin-induced hyperglycemic/diabetic mouse model. Compared to the control group (CON group), hyperglycemic mice exhibited a significant increase in liver injury and intrahepatic inflammation following IR. KCs obtained from hyperglycemic mice secreted higher levels of the pro-inflammatory factors TNF-α and IL-6, while they secreted significantly lower levels of the anti-inflammatory factor 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 anti-inflammatory IL-10 secretion in the hyperglycemic group, while no significant changes in cytokine production were observed in the CON group. We also analyzed the role of hyperglycemia in macrophage M1/M2 polarization. Interestingly, we found that 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. Our results demonstrate that hyperglycemia induces hyper-inflammatory activation of KCs during liver IR injury. Thus, hyperglycemia-induced CHOP over-activation inhibits IL-10-secreting M2-like macrophage polarization by liver-resident macrophages, thereby leading to excessive inflammation and the 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.

Vitamin D Receptor Activation in Liver Macrophages Protects Against Hepatic Endoplasmic Reticulum Stress in Mice

“…(17) Similarly, both IRE1α and CHOP have been found to suppress M2-like polarization of liver-resident macrophages, leading to excessive inflammation and exacerbation of liver injury. (16,18) In the present study, VDR deficiency increased expression of proinflammatory activation markers and decreased induction of alternative macrophage activation markers in the liver. In vitro experiments demonstrate that VDR activation inhibits proinflammatory activation and facilitates alternative polarization in BMDMs treated with ER-stress CM.…”

“…In contrast, macrophage‐specific deletion of IRE1α restores the M2 polarization and decreases levels of proinflammatory cytokines . Similarly, both IRE1α and CHOP have been found to suppress M2‐like polarization of liver‐resident macrophages, leading to excessive inflammation and exacerbation of liver injury . In the present study, VDR deficiency increased expression of proinflammatory activation markers and decreased induction of alternative macrophage activation markers in the liver.…”

“…In turn, deletion of key inflammatory mediators reduces ER stress and protects against liver disease progression . Recent studies also demonstrated that ER stress inhibits the functional shift from proinflammatory to restorative activation of macrophages . However, the interactions between HCs and macrophages during ER stress in both cell types’ response remain unclear.…”

HMGB1‐associated necroptosis and Kupffer cells M1 polarization underlies remote liver injury induced by intestinal ischemia/reperfusion in rats

“…What's more, HMGB1 neutralization treatment further protects against intestinal ischemia-associated liver damage in antibiotic induced microbiota-depleted rats CHOP over-activation inhibited M2 KCs polarization, leading to excessive intrahepatic inflammation and exacerbation of liver I/R injury. 59 Another research also found that spermine-mediated autophagy inhibits M1 polarization but promoting M2 polarization of KCs leading to attenuated thioacetamide-induced liver injury. 60 Previous researches already demonstrated that systemic depletion of macrophages prevents hippocampal neuroinflammation and memory dysfunction after experimental tibial fracture, 61 improves renal I/R injury, 62 and decreases inflammatory mediators in endotoxin-treated rats.…”

Spermine Alleviates Acute Liver Injury by Inhibiting Liver-Resident Macrophage Pro-Inflammatory Response Through ATG5-Dependent Autophagy

“…The role of KC M1/M2 polarization in different liver diseases and injuries has been reported in many studies. A recent study showed that in a mouse liver ischemia/reperfusion model, hyperglycemia-induced CHOP over-activation inhibited KC M2 polarization, leading to excessive intrahepatic inflammation and exacerbation of liver IR injury ( 43 ). Nogo-B was shown to be permissive for M1 polarization in KCs by inhibiting ER stress, thereby accentuating liver injury in alcoholic liver disease in humans and mice ( 44 ).…”