Hepatic immunophenotyping for streptozotocin-induced hyperglycemia in mice

Abstract

Emerging evidence revealed that diabetes induces abnormal immune responses that result in serious complications in organs. However, the effect of hyperglycemia on hepatic immunity remains obscure. We evaluated the population and function of hepatic immune cells in streptozotocin (STZ)-induced hyperglycemic mice. CC chemokine receptor 2 (CCR2)-knockout mice and mice with a depletion of regulatory T cells (DEREG) were used to investigate the migration and role of regulatory T cells (Tregs) in hyperglycemic mice. The inflammatory cytokines and hepatic transaminase levels were significantly increased in the hyperglycemic mice. The population and number of infiltrating monocytes, granulocytes, and Tregs were enhanced in the livers of the hyperglycemic mice. Hepatic monocytes other than macrophages showed the increased expression of inflammatory cytokines and chemokines in the hyperglycemic mice. The CCR2 knockout and DEREG chimeric mice exhibited increased populations of activated T cells and neutrophils compared to the WT chimeric mice, which promoted hepatic inflammation in the hyperglycemic mice. The migration of CCR2 knockout Tregs into the liver was significantly reduced compared to the WT Tregs. We demonstrated that hyperglycemia contributes to increase in infiltrating monocytes and Tregs, which are associated with hepatic immune dysfunction in mice. CCR2-mediated migration of Tregs regulates hyperglycemia-induced hepatic inflammation.

GDF15 deficiency exacerbates chronic alcohol- and carbon tetrachloride-induced liver injury

“…Liver mononuclear cells (MNCs) were isolated as described previously 5 , 23 . Briefly, liver tissues were cut into small pieces and incubated with pre-warmed media containing dissociation enzymes (Miltenyi Biotec, Bergisch Gladbach, Germany) for 30 minutes at 37 °C.…”

“…These immune cells play important roles in the development of hepatic inflammation, steatohepatitis, and fibrotic liver diseases 3 , 4 . Hepatic macrophages have been implicated in the inflammation induced by hyperglycemia in mice 5 . Natural killer T cells and gamma delta T cells are involved in alcoholic liver injury and hepatic fibrosis, respectively 6 , 7 .…”

Hepatic Immune Microenvironment in Alcoholic and Nonalcoholic Liver Disease

“…These discrepancies may be related to the duration or time point of KC depletion in the liver and differences in depletion methodologies or knockout mice. In streptozotocin-induced hyperglycemia, infiltrating monocytes (CD11b + F4/80 int ) and neutrophils were enhanced, but KCs were unchanged in the liver [ 7 ]. Infiltrating hepatic monocytes from mice with streptozotocin-induced hyperglycemia showed higher expression of TNF- α , IL-1 β , IFN- γ , and IL-6 compared to those in control mice.…”

“…Liver resident macrophages, known as Kupffer cells (KCs), account for 20% of nonparenchymal cells in the liver; they are involved in the innate immune response, leading to pathogen clearance by enhancing phagocytic activity [ 6 ]. Infiltrating monocytes, accounting for approximately 5% of nonparenchymal cells, have been implicated in hyperglycemia in mice [ 7 ]. Moreover, eosinophils, comprising 1-2% nonparenchymal cells, are known to activate liver regeneration by secreting interleukin- (IL-) 4 [ 8 ].…”

Long-term apoptosis-related protein expression in the diabetic mouse ovary

“…Chronically high glucose levels have deleterious effects on the structure and function of various organs [ 2 – 4 ]. Tissue damage has been related to the increased formation of advanced glycation end products (AGEs) [ 5 , 6 ] and the overproduction of reactive oxygen species (ROS) [ 2 , 5 ], which can cause oxidative stress, vascular endothelial cell damage and inflammatory cytokine production [ 3 , 7 , 8 ]. Among women with DM, menstrual complications, such as polymenorrhea, oligomenorrhea and amenorrhea followed by ovulation failure, have been described [ 9 , 10 ].…”