Chronic hyperglycemia regulates microglia polarization through ERK5

Chen, Congde; Wu, Suichun; Hong, Zipu; Chen, Xiaoming; Shan, Xiaoou; Fischbach, Shane; Xiao, Xiangwei

doi:10.18632/aging.101770

Cited by 28 publications

(29 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inflammation plays a central role in the onset and progression of diabetic retinopathy ( Tang and Kern, 2011 ; Semeraro et al, 2015 ). Much of the innate immune receptor signaling that elicits inflammation flows through the ERK5 signaling cascade ( Wang and Tournier, 2006 ; Stecca and Rovida, 2019 ), which is increased in Type II diabetics ( Chen et al, 2019 ), and our data suggest in the retina of STZ-diabetic mice. Additionally, ERK5 can induce and enhance the production of multiple growths factors; including VEGF ( Stecca and Rovida, 2019 ).…”

Section: Discussionsupporting

confidence: 57%

“…The cause of diabetic retinopathy is multifactorial, and an optimal therapeutic would halt multiple inflammatory processes, decrease VEGF production, cease neural cell dysfunction, and ablate vascular impairment. Extracellular signal-related kinase 5 (ERK5) is a mitogen-activated protein kinase (MAPK) that elicits the production of multiple inflammatory cytokines and enhances VEGF production in many inflammatory disorders and in diabetes ( Kondoh et al, 2006 ; Wang and Tournier, 2006 ; Hayashi et al, 2004 ; Dorado et al, 2008 ; Chen et al, 2019 ). ERK5 is the terminal member of a MAPK signaling pathway that can induce inflammation through a series of phosphorylation cascades.…”

Section: Introductionmentioning

confidence: 99%

“…When phosphorylated, pERK5 translocates to the nucleus and can induce gene transcription of growth factors and inflammatory cytokines ( Stecca and Rovida, 2019 ; Kondoh et al, 2006 ). Previous studies provide evidence that pERK5 is increased in Type II diabetics, enhances diabetes-mediated neural degeneration, and plays a pathologic role in diabetic nephropathy ( Suzaki et al, 2004 ; Chen et al, 2019 ). In our current studies, we provide evidence that suggests pERK5 is increased in the retina of STZ (streptozotocin)-induced diabetic mice when compared to non-diabetic C57BL/6 mice.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Retinal Inflammation, Oxidative Stress, and Vascular Impairment Is Ablated in Diabetic Mice Receiving XMD8-92 Treatment

et al. 2021

View full text Add to dashboard Cite

The global number of diabetics continues to rise annually. As diabetes progresses, almost all of Type I and more than half of Type II diabetics develop diabetic retinopathy. Diabetic retinopathy is a microvascular disease of the retina, and is the leading cause of blindness in the working-age population worldwide. With such a significant health impact, new drugs are required to halt the blinding threat posed by this visual disorder. The cause of diabetic retinopathy is multifactorial, and an optimal therapeutic would halt inflammation, cease photoreceptor cell dysfunction, and ablate vascular impairment. XMD8-92 is a small molecule inhibitor that blocks inflammatory activity downstream of ERK5 (extracellular signal-related kinase 5) and BRD4 (bromodomain 4). ERK5 elicits inflammation, is increased in Type II diabetics, and plays a pathologic role in diabetic nephropathy, while BRD4 induces retinal inflammation and plays a role in retinal degeneration. Further, we provide evidence that suggests both pERK5 and BRD4 expression are increased in the retinas of our STZ (streptozotocin)-induced diabetic mice. Taken together, we hypothesized that XMD8-92 would be a good therapeutic candidate for diabetic retinopathy, and tested XMD8-92 in a murine model of diabetic retinopathy. In the current study, we developed an in vivo treatment regimen by administering one 100 μL subcutaneous injection of saline containing 20 μM of XMD8-92 weekly, to STZ-induced diabetic mice. XMD8-92 treatments significantly decreased diabetes-mediated retinal inflammation, VEGF production, and oxidative stress. Further, XMD8-92 halted the degradation of ZO-1 (zonula occludens-1), which is a tight junction protein associated with vascular permeability in the retina. Finally, XMD8-92 treatment ablated diabetes-mediated vascular leakage and capillary degeneration, which are the clinical hallmarks of non-proliferative diabetic retinopathy. Taken together, this study provides strong evidence that XMD8-92 could be a potentially novel therapeutic for diabetic retinopathy.

show abstract

Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Retinal Inflammation, Oxidative Stress, and Vascular Impairment Is Ablated in Diabetic Mice Receiving XMD8-92 Treatment

et al. 2021

View full text Add to dashboard Cite

show abstract

“…To support this assumption, in vitro studies have provided evidence for glucose regulation of microglial activity. An elevated glucose concentration induces a morphological change from resting ramified microglia to activated ameboid microglia and stimulates expression and release of pro-inflammatory cytokines by primary microglia, BV-2 cells, and HMC3 cells [ 16 , 17 , 18 , 19 , 20 , 33 , 34 ]. The present study demonstrated that both the primary mouse microglia and SIM-A9 cells responded to increased concentrations of glucose as represented by increased expressions of c-Fos and pERK1/2.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Fructose Transporter Gene Slc2a5 Expression by Glucose in Cultured Microglial Cells

Mizuno

Lew

Jhanji

2021

IJMS

View full text Add to dashboard Cite

Microglia play a role in the regulation of metabolism and pathogenesis of obesity. Microglial activity is altered in response to changes in diet and the body’s metabolic state. Solute carrier family 2 member 5 (Slc2a5) that encodes glucose transporter 5 (GLUT5) is a fructose transporter primarily expressed in microglia within the central nervous system. However, little is known about the nutritional regulation of Slc2a5 expression in microglia and its role in the regulation of metabolism. The present study aimed to address the hypothesis that nutrients affect microglial activity by altering the expression of glucose transporter genes. Murine microglial cell line SIM-A9 cells and primary microglia from mouse brain were exposed to different concentrations of glucose and levels of microglial activation markers and glucose transporter genes were measured. High concentration of glucose increased levels of the immediate-early gene product c-Fos, a marker of cell activation, Slc2a5 mRNA, and pro-inflammatory cytokine genes in microglial cells in a time-dependent manner, while fructose failed to cause these changes. Glucose-induced changes in pro-inflammatory gene expression were partially attenuated in SIM-A9 cells treated with the GLUT5 inhibitor. These findings suggest that an increase in local glucose availability leads to the activation of microglia by controlling their carbohydrate sensing mechanism through both GLUT5-dependent and –independent mechanisms.

show abstract

“…However, excessive activation may lead to the release of inflammatory cytokines, chemokines, reactive oxygen species, and nitric oxide, which can lead to neuronal dysfunction and death [ 80 , 81 , 82 , 83 ]. Exposure to chronic hyperglycemia has been associated with activation of microglia [ 84 ]. Furthermore, when studying the mouse microglial BV-2 cell line, exposure to glucose fluctuations resulted in increased markers of metabolic stress leading to apoptosis and/or autophagy [ 85 ] as well as leading to shifts in microglial polarization to the inflammatory M1 phenotype [ 53 ].…”

Section: Impact Of Gv On Central Nervous System Inflammationmentioning

confidence: 99%

Glycemic Variability and CNS Inflammation: Reviewing the Connection

2020

View full text Add to dashboard Cite

Glucose is the primary energy source for the brain, and exposure to both high and low levels of glucose has been associated with numerous adverse central nervous system (CNS) outcomes. While a large body of work has highlighted the impact of hyperglycemia on peripheral and central measures of oxidative stress, cognitive deficits, and vascular complications in Type 1 and Type 2 diabetes, there is growing evidence that glycemic variability significantly drives increased oxidative stress, leading to neuroinflammation and cognitive dysfunction. In this review, the latest data on the impact of glycemic variability on brain function and neuroinflammation will be presented. Because high levels of oxidative stress have been linked to dysfunction of the blood–brain barrier (BBB), special emphasis will be placed on studies investigating the impact of glycemic variability on endothelial and vascular inflammation. The latest clinical and preclinical/in vitro data will be reviewed, and clinical/therapeutic implications will be discussed.

show abstract

Chronic hyperglycemia regulates microglia polarization through ERK5

Cited by 28 publications

References 26 publications

Retinal Inflammation, Oxidative Stress, and Vascular Impairment Is Ablated in Diabetic Mice Receiving XMD8-92 Treatment

Retinal Inflammation, Oxidative Stress, and Vascular Impairment Is Ablated in Diabetic Mice Receiving XMD8-92 Treatment

Regulation of the Fructose Transporter Gene Slc2a5 Expression by Glucose in Cultured Microglial Cells

Glycemic Variability and CNS Inflammation: Reviewing the Connection

Contact Info

Product

Resources

About