Activation of Macrophages and Microglia by Interferon–γ and Lipopolysaccharide Increases Methylglyoxal Production: A New Mechanism in the Development of Vascular Complications and Cognitive Decline in Type 2 Diabetes Mellitus?

Dhananjayan, Karthik; Gunawardena, Dhanushka; Hearn, Nerissa L.; Sonntag, Tanja; Moran, Chris; Gyengési, Erika; Srikanth, Velandai; Münch, Gerald

doi:10.3233/jad-161152

Cited by 20 publications

(15 citation statements)

References 169 publications

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“…The activation of the methylglyoxal pathway and production of this metabolite has been associated with the induction of a proinflammatory phenotype in macrophages [ 86 ]. In addition, activation of macrophages and microglia with a combination of LPS and IFN-γ reportedly leads to the production and secretion of methylglyoxal [ 87 ].…”

Section: Discussionmentioning

confidence: 99%

β-Hydroxybutyrate Oxidation Promotes the Accumulation of Immunometabolites in Activated Microglia Cells

et al. 2020

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Metabolic regulation of immune cells has arisen as a critical set of processes required for appropriate response to immunological signals. While our knowledge in this area has rapidly expanded in leukocytes, much less is known about the metabolic regulation of brain-resident microglia. In particular, the role of alternative nutrients to glucose remains poorly understood. Here, we use stable-isotope (13C) tracing strategies and metabolomics to characterize the oxidative metabolism of β-hydroxybutyrate (BHB) in human (HMC3) and murine (BV2) microglia cells and the interplay with glucose in resting and LPS-activated BV2 cells. We found that BHB is imported and oxidised in the TCA cycle in both cell lines with a subsequent increase in the cytosolic NADH:NAD+ ratio. In BV2 cells, stimulation with LPS upregulated the glycolytic flux, increased the cytosolic NADH:NAD+ ratio and promoted the accumulation of the glycolytic intermediate dihydroxyacetone phosphate (DHAP). The addition of BHB enhanced LPS-induced accumulation of DHAP and promoted glucose-derived lactate export. BHB also synergistically increased LPS-induced accumulation of succinate and other key immunometabolites, such as α-ketoglutarate and fumarate generated by the TCA cycle. Finally, BHB upregulated the expression of a key pro-inflammatory (M1 polarisation) marker gene, NOS2, in BV2 cells activated with LPS. In conclusion, we identify BHB as a potentially immunomodulatory metabolic substrate for microglia that promotes metabolic reprogramming during pro-inflammatory response.

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Section: Discussionmentioning

confidence: 99%

β-Hydroxybutyrate Oxidation Promotes the Accumulation of Immunometabolites in Activated Microglia Cells

et al. 2020

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“…Monocytes/macrophages play an important role in the occurrence and development of T2DM, which is regarded as a type of low-grade inflammation (4,5,30,31). The in vitro results of our previous study using RAW264.7 macrophages revealed that uc.48+ siRNA is able to regulate immune and inflammatory responses, thus influencing the course and outcome of these effects, which are mediated by the P2X 7 receptor (13).…”

Section: Discussionmentioning

confidence: 99%

lncRNA uc.48+ regulates immune and inflammatory reactions mediated by the P2X7 receptor in type 2 diabetic mice

Jiang

Liu

et al. 2020

Exp Ther Med

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Diabetes and non-coding RNAs are receiving increasing attention in contemporary medical research. The present study aimed to explore the role of the long non-coding RNA uc.48+ in the pathological changes of type 2 diabetes mellitus (T2DM) by observing the effects of uc.48+ small interfering RNA (siRNA) on the abdominal cells of a mouse model of T2DM. Mice with T2DM (DM group) were established by feeding with a high-sugar and-fat diet combined with intraperitoneal injections of low-dose streptozotocin. An intraperitoneal injection of uc.48+ siRNA was administered to the diabetic mice, and the serum levels of cytokines together with other clinical parameters, namely blood pressure, heart rate, mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were examined. Following the collection and identification of abdominal cells from the mice, the mRNA levels of uc.48+, mRNA and protein levels of the P2X 7 receptor, and phosphorylation levels of ERK1/2 were evaluated by reverse transcription-PCR and western blotting, respectively. The MWT and TWL were significantly decreased in the DM group compared with the non-diabetic control group. However, the reductions in MWT and TWL were significantly attenuated following uc.48+ siRNA injection. The systolic and diastolic blood pressure, as well as the serum levels of tumor necrosis factor α and interleukin 1β of mice in the DM group were significantly increased compared with those in the control group, whereas these changes were significantly attenuated following the injection of uc.48+ siRNA. In addition, the expression levels of P2X 7 receptor mRNA and protein, and the degree of phosphorylation of ERK1/2 in the abdominal cells were significantly increased in the DM group compared with the control group. These changes were also significantly attenuated following transfection with uc.48+ siRNA in vivo. In conclusion, these data suggest that uc.48+ may play an important role in the pathological changes of blood pressure, neurology and abdominal cell function in T2DM via interaction with the P2X 7 receptor.

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“…One example of this phenomenon is through increased activation of the first enzyme of the glycolytic pathway, hexokinase. 50 LPS also activates the transcription factor hypoxia-inducible factor 1 alpha (HIF-1 ), 49 46 A prerequisite of protein nitrotyrosination is the interaction of proteins with nitrating agents such as peroxynitrite. 72 Peroxynitrite forms in the presence of the ROS, superoxide (O 2 − ), and the reactive nitrogen species, Nitric Oxide, 73 all induced in M1 macrophages.…”

Section: Discussionmentioning

confidence: 99%

Classically activated mouse macrophages produce methylglyoxal that induces a TLR4- and RAGE-independent proinflammatory response

Prantner

Nallar

Richard

et al. 2020

Journal of Leukocyte Biology

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The highly reactive compound methylglyoxal (MG) can cause direct damage to cells and tissues by reacting with cellular macromolecules. MG has been identified as a biomarker associated with increased sepsis-induced mortality. Patients undergoing septic shock have significantly elevated circulating MG levels compared to postoperative patients and healthy controls. Furthermore, MG has been implicated in the development of type II diabetes mellitus and Alzheimer's disease. Because MG is generated during glycolysis, we hypothesized that MG may be produced by classically activated (M1) macrophages, possibly contributing to the inflammatory response. LPS and IFN-treated macrophages acquired an M1 phenotype (as evidenced by M1 markers and enhanced glycolysis) and formed MG adducts, MG-H1, MG-H2, and MG-H3, which were detected using antibodies specific for MG-modified proteins (methylglyoxal 5hydro-5-methylimidazolones). MG adducts were also increased in the lungs of LPS-treated mice. Macrophages treated with LPS and IFN-also exhibited decreased expression of glyoxalase 1 (Glo1), an enzyme that metabolizes MG. Concentrations of exogenous, purified MG > 0.5 mM were toxic to macrophages; however, a nontoxic dose of 0.3 mM induced TNF-and IL-1 , albeit to a lesser extent than LPS stimulation. Despite prior evidence that MG adducts may signal through "receptor for advanced glycation endproducts" (RAGE), MG-mediated cell death and cytokine induction by exogenous MG was RAGE-independent in primary macrophages. Finally, RAGE-deficient mice did not exhibit a significant survival advantage following lethal LPS injection. Overall, our evidence suggests that MG may be produced by M1 macrophages during sepsis, following IFN-dependent down-regulation of Glo1, contributing to over-exuberant inflammation.

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Activation of Macrophages and Microglia by Interferon–γ and Lipopolysaccharide Increases Methylglyoxal Production: A New Mechanism in the Development of Vascular Complications and Cognitive Decline in Type 2 Diabetes Mellitus?

Cited by 20 publications

References 169 publications

β-Hydroxybutyrate Oxidation Promotes the Accumulation of Immunometabolites in Activated Microglia Cells

β-Hydroxybutyrate Oxidation Promotes the Accumulation of Immunometabolites in Activated Microglia Cells

lncRNA uc.48+ regulates immune and inflammatory reactions mediated by the P2X7 receptor in type 2 diabetic mice

Classically activated mouse macrophages produce methylglyoxal that induces a TLR4- and RAGE-independent proinflammatory response

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