Heparin inhibits proinflammatory and promotes anti-inflammatory macrophage polarization under hyperglycemic stress

Abstract

Monocytes are rapidly recruited to sites of diabetic complications and differentiate into macrophages. Previously, we showed that rat kidney mesangial cells dividing during hyperglycemic stress abnormally synthesize hyaluronan (HA) in intracellular compartments. This initiates a stress response, resulting in an extracellular HA matrix after division that recruits inflammatory cells. Cell–cell communication among macrophages that are recruited into the glomeruli and the damaged rat mesangial cells leads to diabetic nephropathy, fibrosis, and proteinurea, which are inhibited in heparin-treated diabetic rats. In this study, we found that murine bone marrow–derived macrophages (BMDMs) and a human leukemic cell line, U937 cells, dividing in hyperglycemia also accumulate intracellular HA and that heparin inhibits the HA accumulation. Both cell types expressed increased levels of proinflammatory markers: inducible nitric-oxide synthase and tumor necrosis factor-α, when cultured under hyperglycemic stress, which was inhibited by heparin. Furthermore, the abnormal intracellular HA was also observed in peripheral blood monocytes derived from three different hyperglycemic diabetic mouse models: streptozotocin-treated, high-fat fed, and Ins2Akita. Moreover, peripheral blood monocytes in humans with type 2 diabetes and poorly controlled blood glucose levels (hemoglobin A1c (HbA1c) levels of >7) also had intracellular HA, whereas those with HbA1c of <7, did not. Of note, heparin increased the anti-inflammatory markers arginase 1 and interleukin-10 in murine BMDMs. We conclude that heparin treatment of high glucose–exposed dividing BMDMs promotes an anti-inflammatory tissue-repair phenotype in these cells.

Distinct Effects of Heparin and Interleukin‐4 Functionalization on Macrophage Polarization and In Situ Arterial Tissue Regeneration Using Resorbable Supramolecular Vascular Grafts in Rats

“…[ 61 ] Moreover, when exposed to macrophages, they showed that heparin locally sequesters the macrophage produced growth factors. While potential effects of heparin by itself on macrophage polarization have been suggested, [ 62 ] no clear effect of heparin on macrophage polarization was observed as the bare and heparin group both showed a trend toward more M1 (iNOS+) macrophages and lower M2 (Arg+) macrophages, which is in correspondence to our previous in vitro data on this materials. [ 23 ] This may explain why we did not observe hyperplasia in the IL‐4/hep dual‐functionalized group, as the growth factor and cytokine release profile would be altered by the IL‐4‐induced macrophage polarization, although this warrants further investigation.…”

Influence of Optimal Management of Hyperglycemia and Intensive Nursing on Blood Glucose Control Level and Complications in Patients with Postoperative Cerebral Hemorrhage

“…The results suggest that the intensive nursing of hyperglycemia optimization management can effectively improve the degree of nerve defect and the ability of daily living in patients with cerebral hemorrhage after operation. This is due to the optimal management of hyperglycemia intensive nursing inter-vention mode of patients with better blood glucose control can avoid hyperglycemia damage to neurons [27][28][29]. Hyperglycemia can increase the anaerobic metabolism of brain tissue, destroy mitochondria, produce a large number of free radicals, and increase the Ca2 + influx of nerve cells [30][31][32].…”

Systemic Inflammation and COVID-19 Mortality in Patients with Major Noncommunicable Diseases: Chronic Coronary Syndromes, Diabetes and Obesity

“…Moreover, hyperglycemia seems to be involved in the “trained immunity” (the nonspecific, immunological memory of past insults) through epigenetic modifications that sustain inflammation and transcriptional activation of genes involved in atherosclerosis [ 101 , 104 ]. Interestingly, on the other hand, heparin inhibits the proinflammatory polarization of macrophages in hyperglycemic conditions and promotes an anti-inflammatory phenotype of these cells [ 105 ].…”