Hyperglycaemia amplifies TLR-mediated inflammatory response of M(IL4) macrophages to dyslipidemic ligands.

Hyperglycaemia is critical for initiation of diabetic vascular complications. We systemically addressed the role of hyperglycaemia in the regulation of TLRs in primary human macrophages. Expression of TLRs (1-9) was examined in monocyte-derived M(NC), M(IFNγ) and M(IL4) differentiated in normoglycemic and hyperglycaemic conditions. Hyperglycaemia increased expression of TLR1 and TLR8 in M(NC), TLR 2 and 6 in M(IFNγ), and TLR4 and TLR5 in M(IL4). The strongest effect of hyperglycaemia in M(IL4) was the upregulation of TLR4 gene and protein expression. Hyperglycaemia amplified TLR4-mediated response of M(IL4) to LPS by significantly enhancing IL1beta and modestly supressing IL10 production. In M(IL4), hyperglycaemia in combination with synthetic triacylated lipopeptide (TLR1/TLR2 ligand), amplified expression of TLR4, and production of IL1beta. In summary, hyperglycaemia enhanced inflammatory potential of homeostatic, inflammatory and healing macrophages by increasing specific profiles of TLRs. In combination with dyslipidemic ligands, hyperglycaemia can stimulate low-grade inflammatory program in healing macrophages supporting vascular diabetic complications.