Advanced Glycation End Products Enhance Macrophages Polarization into M1 Phenotype through Activating RAGE/NF-κB Pathway

Abstract

Atherosclerotic lesions are accelerated in patients with diabetes. M1 (classically activated in contrast to M2 alternatively activated) macrophages play key roles in the progression of atherosclerosis. Since advanced glycation end products (AGEs) are major pathogenic factors and active inflammation inducers in diabetes mellitus, this study assessed the effects of AGEs on macrophage polarization. The present study showed that AGEs significantly promoted macrophages to express IL-6 and TNF-α. M1 macrophage markers such as iNOS and surface markers including CD11c and CD86 were significantly upregulated while M2 macrophage markers such as Arg1 and CD206 remained unchanged after AGEs stimulation. AGEs significantly increased RAGE expression in macrophages and activated NF-κB pathway, and the aforementioned effects were partly abolished by administration of anti-RAGE antibody or NF-κB inhibitor PDTC. In conclusion, our results suggest that AGEs enhance macrophage differentiation into proinflammatory M1 phenotype at least partly via RAGE/NF-κB pathway activation.

AGEs Induced Autophagy Impairs Cutaneous Wound Healing via Stimulating Macrophage Polarization to M1 in Diabetes

“…Synthetic ALE could increase the expression of IL-6, IL-8, MCP-1, and iNOS in induced THP-1 monocytes32. Furthermore, AGEs enhanced BMDM cells polarization into M1 macrophage with producing IL-6 and TNF-a proinflammatory cytokines and upregulating the expressions of CD11c and CD86 through activating RAGE/NF-κB pathway in mice33. In addition, AGEs has been shown to induce autophagy in some cells, such as hepatic stellate cells34, cardimyocytes35, vascular smooth muscle cells36, and endothelial cells37.…”

Proinflammatory monocyte polarization in type 2 diabetes mellitus and coronary heart disease

“…In its turn, protein kinase C is responsible for the activation of NF-kB [17] contributing to improvements in adhesion of monocytes to the vascular wall [17,18] . Jin et al [19] found that AGEs not only predominantly induce macrophages to secrete inflammatory cytokines, but also induce M1 polarization. Moreover, AGEs activate the RAGE/NF-kB pathway, whereas the blockade of RAGE or NF-kB can attenuate macrophage activation [19,20] .…”

“…Jin et al [19] found that AGEs not only predominantly induce macrophages to secrete inflammatory cytokines, but also induce M1 polarization. Moreover, AGEs activate the RAGE/NF-kB pathway, whereas the blockade of RAGE or NF-kB can attenuate macrophage activation [19,20] . We also found a direct correlation between the levels of HbA1c and TNF-α in patients with newly diagnosed diabetes [ Figure 1].…”

Significance of M1 and M2 Polarization of Monocytes-Macrophages in the Blood for Atherosclerosis Risk Assessment in Type 2 Diabetes Comparing With Coronary Heart Disease

“…Именно ПКС ответ ственна за активиза-цию NFκB способствующего повышению адгезии моноцитов к сосудистой стенке и их дифференци-ровке в макрофаги. Вместе с тем, образующиеся в условиях гипергликемии конечные продукты нефер-ментного гликирования (КПНГ), подавляют противо-воспалительную активность ядерных рецепторов PPARɣ [13], что доказывается выраженным противо-воспалительным эффектом агонистов PPARɣ [14].…”