Differential regulation of aldose reductase expression during macrophage polarization depends on hyperglycemia

Abstract

Aldose reductase (AR; gene AKR1B1) is the rate-limiting enzyme of the polyol pathway and has been associated with diabetes and atherosclerosis. Here, we sought to identify the mechanisms underlying differential AR expression in human atherosclerotic plaque macrophages. In vitro, M1-polarized human monocyte-derived macrophages expressed significantly higher levels of AKR1B1 mRNA and AR protein compared with M2-polarized macrophages. AR activity was significantly higher in M1 macrophages. AKR1B1 mRNA expression correlated positively with the M1 marker TNF(r = 0.430,P = 0.006) and negatively with the M2 marker MRC1 (r = -0.443,P = 0.044). Increased AR expression in M1 macrophages depended on hyperglycemia. Concomitantly, expression of SLC2A1 (coding for the Glc transporter GLUT-1) was significantly higher in M1 than in M2 macrophages. Pharmacological inhibition of GLUT-1 using STF-32 completely abrogated Glc-induced AR up-regulation in M1 macrophages. When analyzing AR expression in post-mortem coronary artery plaque macrophages, a history of diabetes was associated with a significantly increased proportion of CD68(+)AR(++)macrophages, supporting the in vivo relevance of our in vitro findings. We demonstrate that the phenotype of atherosclerotic plaque macrophages may be affected by cardiovascular risk factors such as hyperglycemia. Our data illustrate the complex interplay between systemic and local factors in atherogenesis.

Engagement of monocytes, NK cells, and CD4+ Th1 cells by ALVAC-SIV vaccination results in a decreased risk of SIVmac251 vaginal acquisition

“…In agreement with our prior work, changes in gene expression in the blood of animals in the ALVAC-SIV group (week 26 compared to pre-vaccination) supported the association of classical monocyte cells and inflammasome activation with decreased risk of SIV acquisition (Fig 2C). While no association was observed between SIV acquisition and monocyte frequency in the NYVAC-SIV group, classical monocyte genes associated with the decreased risk conferred by ALVAC-SIV vaccination included AKR1B1 (a marker of M1 macrophage polarization [30]), CCL3 and CDKN1A (monocytic inhibitors of HIV-1 replication [31,32]), CCR2 and CD44 (promotors of monocyte chemotaxis [33,34]), CD14 (the co-receptor of LPS at the surface of monocytes), CLEC7A (an inducer of NLRP3 inflammasome [35]), IL1β (the byproduct of NLRP3 inflammasome activation [36]) and its receptor IL1R2 [37], and F13A1 the three animal groups (ALVAC-SIV, n = 18; NYVAC-SIV, n = 19; pooled controls n = 20). (E) Logarithmic mean ± s.d.…”

Human Aldose Reductase Expression Prevents Atherosclerosis Regression in Diabetic Mice

“…We also demonstrated that pharmacological inhibition of AR reduced lesion size (21). Notably, AR is expressed in CD68 + cells (monocytes/macrophages) from human atherosclerotic plaques (16), and plaques from patients with diabetes had 36% more CD68 + AR + macrophages than patients without diabetes (22).…”

Induction of Osmolyte Pathways in Skeletal Muscle Inflammation: Novel Biomarkers for Myositis

“…It is well known that macrophages have versatile functionalities, with a spectrum stretching out between the classical inflammatory M1 phenotype, to the alternative anti-inflammatory, tissue repair-oriented M2 phenotype ( 53 ). Significantly higher levels of AKR1B1 mRNA and protein have been reported in M1 macrophages compared with M2-polarized macrophages ( 54 ). The upstream transcription factor NFAT5 is enhanced by the M1-promoting pro-inflammatory and hypoxic conditions associated with autoimmune diseases, which is particularly suggested to regulate the chemokine MCP-1 and subsequent synovial macrophage survival in rheumatoid arthritis ( 55 ).…”