Aldose reductase (AKR1B) deficiency promotes phagocytosis in bone marrow derived mouse macrophages

Abstract

Macrophages are critical drivers of the immune response during infection and inflammation. The pathogenesis of several inflammatory conditions, such as diabetes, cancer and sepsis has been linked with aldose reductase (AR), a member of the aldo-keto reductase (AKR) superfamily. However, the role of AR in the early stages of innate immunity such as phagocytosis remains unclear. In this study, we examined the role of AR in regulating the growth and the phagocytic activity of bone marrow-derived mouse macrophages (BMMs) from AR-null and wild-type (WT) mice. We found that macrophages derived from AR-null mice were larger in size and had a slower growth rate than those derived from WT mice. The AR-null macrophages also displayed higher basal, and lipopolysaccharide (LPS) stimulated phagocytic activity than WT macrophages. Moreover, absence of AR led to a marked increase in cellular levels of both ATP and NADPH. These data suggest that metabolic pathways involving AR suppress macrophage energy production, and that inhibition of AR could induce a favorable metabolic state that promotes macrophage phagocytosis. Hence, modulation of macrophage metabolism by inhibition of AR might represent a novel strategy to modulate host defense responses and to modify metabolism to promote macrophage hypertrophy and phagocytosis under inflammatory conditions.

Aldose Reductase Inhibitor Engeletin Suppresses Pelvic Inflammatory Disease by Blocking the Phospholipase C/Protein Kinase C-Dependent/NF-κB and MAPK Cascades

“…36,37 Singh et al demonstrated that the inhibition of AR promoted the phagocytic activity of bone marrow-derived mouse macrophages via increased glycolysis and elevated levels of ATP and NADPH. 25 Our experiments showed that engeletin suppressed AR activity and enhanced the phagocytosis of RAW 264.7 macrophages, which is consistent with the previous studies. However, whether engeletin promotes phagocytosis via the same mechanism is not clear and requires further research.…”

“…Engeletin Promoted Phagocytosis in RAW 264.7 Macrophages. Because previous studies showed that AR deficiency promoted phagocytosis in mouse macrophages, 25 we used the neutral red assay and fluorescence microscopy to determine the effects of engeletin on the phagocytosis of RAW 264.7 macrophages. The neutral red assay demonstrated that engeletin treatment significantly increased the phagocytic activity in cells without LPS exposure, which suggests that engeletin enhances the phagocytic activity of cells at a basal level.…”

Remodeling of Retinal Architecture in Diabetic Retinopathy: Disruption of Ocular Physiology and Visual Functions by Inflammatory Gene Products and Pyroptosis

“…AGE formation can lead to an imbalance in growth factors and inflammation imbalances in the ocular compartment of diabetic patients ( Obrosova and Kador, 2011 ). Further, upregulation of polyol via the hexosamine pathway is also associated with DR ( Sharma et al, 2005 ; Kowluru and Chan, 2007 ; Safi et al, 2014 ; Singh et al, 2017 ).…”

Expression profiles of interferon‐stimulated gene 15 and prostaglandin synthases in the ovine lymph nodes during early pregnancy

“…In this study, the AKR1B1 monomer and dimer were more highly expressed on Day 16 of pregnancy (Figure ). As a member of the aldo‐keto reductase superfamily, aldose reductase (AKR1B) inhibits macrophage phagocytosis in the bone marrow‐derived mouse macrophages (Singh, Kapoor, Mccracken, Hill, & Bhatnagar, ), and macrophages are crucial drivers of the immune response during infection and inflammation. IFNT can block the uterine development of the luteolytic mechanism but does not inhibit the production of PGF2α during pregnancy.…”