Ernesto Badillo (Mannheim/ DE), Quan Liu (Mannheim/ DE), Prof. Dr. Martin C. Harmsen (Groningen/ NL), Prof. Dr. Harald Klüter (Mannheim/ DE), Prof. Dr. Julia Kzhyshkowska (Mannheim/ DE), Lina Susana Silva Bermudez (Mannheim/ DE)
Background
Hyperglycemia (HG) is a critical factor in the initiation of diabetic complications. Macrophages are key innate immune cells that regulate inflammatory responses which are responsible for the development of micro- and macrovascular complications. Increased expression of toll-like receptor 4 (TLR4) has been inked to type 2 diabetes (T2D). Here for the first time, we systemically addressed the role of hyperglycemia in the regulation of TLR system in primary human macrophages.
Methods
Expression of TLR 1-9 was examined in primary human monocyte-derived homeostatic M(NS), inflammatory M1(IFNgamma) and healing M(IL4) macrophages in normoglycemic and hyperglycemic (HG) conditions by RT-PCR and flow cytometry. Cytokine secretion was quantified by ELISA.
Results
HG induced upregulation in expression of TLR1 and TLR8 in M0 macrophages, TLR1, TLR2 and TLR6 in M1, and TLR4 and TLR5 in M2. HG potentiated TLR4-mediated response of M2 to LPS and significantly enhanced production of IL1beta. In M (IL4), HG in combination with PAM3CSK4 (PAM3), synthetic triacylated lipopeptide, ligand for TLR1/TLR2 amplified expression of TLR4, enhanced production of IL1beta, and supressed production of IL10.
Conclusion
We found that hyperglycaemia alone enhances inflammatory potential of homeostatic, inflammatory, and healing macrophages by increasing specific profiles of TLRs. In combination with dyslipidaemic ligands, hyperglycaemia can switch the inflammatory program in healing (M2) macrophages towards supporting vascular inflammatory complications in diabetic patients.
Offenlegung Interessenkonflikt:
No