Badillo-Garcia Luis Ernesto, Liu Quan, Ziebner Kim, Balduff Michael, Sevastyanova Tatyana, Schmuttermaier Christina, Klüter Harald, Harmsen Martin, Kzhyshkowska Julia
Medical Faculty Mannheim, Institute of Transfusion Medicine and Immunology, Institute for Innate Immunoscience (MI3), Heidelberg University, Ludolf-Krehl Strasse 13-17, Mannheim 68167, Germany.
Department of Orthopaedics and Trauma Surgery, Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl Strasse 13-17, Mannheim 68167, Germany.
J Leukoc Biol. 2024 Jun 28;116(1):197-204. doi: 10.1093/jleuko/qiae050.
Hyperglycemia is critical for initiation of diabetic vascular complications. We systemically addressed the role of hyperglycemia 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 hyperglycemic conditions. Hyperglycemia increased expression of TLR1 and TLR8 in M(NC), TLR2 and TLR6 in M(IFNγ), and TLR4 and TLR5 in M(IL4). The strongest effect of hyperglycemia in M(IL4) was the upregulation of the TLR4 gene and protein expression. Hyperglycemia amplified TLR4-mediated response of M(IL4) to lipopolysaccharide by significantly enhancing IL1β and modestly suppressing IL10 production. In M(IL4), hyperglycemia in combination with synthetic triacylated lipopeptide (TLR1/TLR2 ligand) amplified expression of TLR4 and production of IL1β. In summary, hyperglycemia enhanced the inflammatory potential of homeostatic, inflammatory, and healing macrophages by increasing specific profiles of TLRs. In combination with dyslipidemic ligands, hyperglycemia can stimulate a low-grade inflammatory program in healing macrophages supporting vascular diabetic complications.
高血糖对于糖尿病血管并发症的发生至关重要。我们系统地研究了高血糖在原代人巨噬细胞中Toll样受体（TLR）调节中的作用。检测了在正常血糖和高血糖条件下分化的单核细胞来源的M(NC)、M(IFNγ)和M(IL4)中TLR（1-9）的表达。高血糖增加了M(NC)中TLR1和TLR8的表达，M(IFNγ)中TLR2和TLR6的表达，以及M(IL4)中TLR4和TLR5的表达。高血糖对M(IL4)的最强作用是上调TLR4基因和蛋白表达。高血糖通过显著增强IL1β和适度抑制IL10的产生，放大了M(IL4)对脂多糖的TLR4介导的反应。在M(IL4)中，高血糖与合成的三酰化脂肽（TLR1/TLR2配体）联合增强了TLR4的表达和IL1β的产生。总之，高血糖通过增加特定的TLR谱增强了稳态、炎症和愈合巨噬细胞的炎症潜能。与血脂异常配体联合，高血糖可刺激愈合巨噬细胞中的低度炎症程序，支持糖尿病血管并发症。
