Effect of increased glucose on the expression of TLRs in human macrophages: potential mechanism of chronic inflammation in diabetes

Abstract

Diabetic patients suffer from a chronic inflammation regulated by macrophages. M1 and M2 represent two major directions of macrophage functional polarisation. Toll-like receptors (TLR)-mediated response to exogenous and endogenous factors results in pro-inflammatory activation of macrophages. Increased TLR expression in monocytes is associated with the diabetic inflammation and complications. The aim of our study was to examine how elevated glucose levels affect expression of TLRs in M1 and M2. Monocytes were isolated from healthy donors and cultured in serum-free medium in the presence of 5mM or 25mM glucose for 6 days. M1 and M2 differentiation was driven by IFN-γ and IL-4. Quantification of TLR mRNA expression was performed by RT-PCR and demonstrated that mRNA of TLR1, 2, 4, 6 and 8, but not TLR5 and 9, were expressed in M1 and M2. All identified TLRs were expressed on higher levels in M1 compared to M2 in low and high glucose conditions. Increased glucose had most pronounced stimulatory effect on the expression of TLR2 and less on TLR6. In individual M1 cultures high glucose stimulated up to 8-fold increase of TLR2 and up to 28% increased of TLR6 expression. In M2, TLR2 expression was up to 6-fold higher in the presence to high glucose. High glucose had suppressive effect on the expression of TLR4 (in 5 of 8 donors up to 65%) in M1 and M2. We concluded that glucose regulates TLR2, 6 and 4 expression in a donor-specific way. This may explain the individual development of inflammation-mediated complications in diabetes.