scholarly journals Interplay between Müller cells and microglia aggravates retinal inflammatory response in experimental glaucoma

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Xin Hu ◽  
Guo-Li Zhao ◽  
Meng-Xi Xu ◽  
Han Zhou ◽  
Fang Li ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Glial Cells ◽  
Cell Activation ◽  
Ganglion Cells ◽  
Müller Cells ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Inflammatory Factors ◽  
Muller Cells ◽  
Protein Levels ◽  
Experimental Glaucoma

Abstract Background Glaucoma, the leading cause of irreversible blindness, is a retinal neurodegenerative disease, which results from progressive apoptotic death of retinal ganglion cells (RGCs). Although the mechanisms underlying RGC apoptosis in glaucoma are extremely complicated, an abnormal cross-talk between retinal glial cells and RGCs is generally thought to be involved. However, how interaction of Müller cells and microglia, two types of glial cells, contributes to RGC injury is largely unknown. Methods A mouse chronic ocular hypertension (COH) experimental glaucoma model was produced. Western blotting, immunofluorescence, quantitative real-time polymerase chain reaction (q-PCR), transwell co-culture of glial cells, flow cytometry assay, ELISA, Ca2+ image, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) techniques were employed to investigate the interaction of Müller cells and microglia, and its underlying mechanisms in COH retina. Results We first showed that Müller cell activation in mice with COH induced microglia activation through the ATP/P2X7 receptor pathway. The activation of microglia resulted in a significant increase in mRNA and protein levels of pro-inflammatory factors, such as tumor necrosis factor-α and interleukin-6. These inflammatory factors in turn caused the up-regulation of mRNA expression of pro-inflammatory factors in Müller cells through a positive feedback manner. Conclusions These findings provide robust evidence, for the first time, that retinal inflammatory response may be aggravated by an interplay between activated two types of glial cells. These results also suggest that to reduce the interplay between Müller cells and microglia could be a potential effective strategy for preventing the loss of RGCs in glaucoma.

scholarly journals A dialogue between glia and neurons in the retina: modulation of neuronal excitability

2004 ◽  
Vol 1 (3) ◽  
pp. 245-252 ◽  
Author(s):  
ERIC A. NEWMAN
Keyword(s):  
Synaptic Transmission ◽  
Glial Cells ◽  
Neuronal Excitability ◽  
Ganglion Cells ◽  
Brain Slices ◽  
Müller Cells ◽  
Muller Cells ◽  
Signaling Mechanisms ◽  
Bidirectional Signaling ◽  
Stimulation Of

Bidirectional signaling between neurons and glial cells has been demonstrated in brain slices and is believed to mediate glial modulation of synaptic transmission in the CNS. Our laboratory has characterized similar neuron–glia signaling in the mammalian retina. We find that light-evoked neuronal activity elicits Ca2+ increases in Müller cells, which are specialized retinal glial cells. Neuron to glia signaling is likely mediated by the release of ATP from neurons and is potentiated by adenosine. Glia to neuron signaling has also been observed and is mediated by several mechanisms. Stimulation of glial cells can result in either facilitation or depression of synaptic transmission. Release of D-serine from Müller cells might also potentiate NMDA receptor transmission. Müller cells directly inhibit ganglion cells by releasing ATP, which, following hydrolysis to adenosine, activates neuronal A1 receptors. The existence of bidirectional signaling mechanisms indicates that glial cells participate in information processing in the retina.

scholarly journals Characteristics of Müller glial cells in MNU-induced retinal degeneration

2016 ◽  
Vol 33 ◽  
Author(s):  
MIRIAM REISENHOFER ◽  
THOMAS PANNICKE ◽  
ANDREAS REICHENBACH ◽  
VOLKER ENZMANN
Keyword(s):  
Glial Cells ◽  
Cell Activation ◽  
Ischemia Reperfusion ◽  
Outer Nuclear Layer ◽  
Müller Cells ◽  
Müller Cell ◽  
Reactive Gliosis ◽  
Muller Cells ◽  
Müller Glial Cells ◽  
Muller Cell

AbstractRetinal Müller glial cells have been shown to undergo reactive gliosis in a variety of retinal diseases. Upregulation of glial fibrillary acidic protein (GFAP) is a hallmark of Müller cell activation. Reactive gliosis after retinal detachment or ischemia/reperfusion is characterized by hypertrophy and downregulation of inwardly rectifying K+ (Kir) currents. However, this kind of physiological alteration could not be detected in slowly progressing retinal degenerations. The photoreceptor toxin N-methyl-N-nitrosourea (MNU) leads to the rapid loss of cells in the outer nuclear layer and subsequent Müller cell activation. Here, we investigated whether Müller cells from MNU-treated mice exhibit reactive gliosis. We found that Müller cells showed increased GFAP expression and increased membrane capacitance, indicating hypertrophy. Membrane potential and Kir channel-mediated K+ currents were not significantly altered whereas Kir4.1 mRNA expression and Kir-mediated inward current densities were markedly decreased. This suggests that MNU-induced Müller cell gliosis is characterized by plasma membrane increase without alteration in the membrane content of Kir channels. Taken together, our findings show that Müller cells of MNU-treated mice are reactive and respond with a form of gliosis which is characterized by cellular hypertrophy but no changes in Kir current amplitudes.

scholarly journals Aerobic Exercise Inhibits CUMS-Depressed Mice Hippocampal Inflammatory Response via Activating Hippocampal miR-223/TLR4/MyD88-NF-κB Pathway

2020 ◽  
Vol 17 (8) ◽  
pp. 2676 ◽  
Author(s):  
Honglin Qu ◽  
Ruilian Liu ◽  
Jiaqin Chen ◽  
Lan Zheng ◽  
Rui Chen
Keyword(s):  
Inflammatory Response ◽  
Aerobic Exercise ◽  
Exercise Group ◽  
Inflammatory Factors ◽  
Control Group ◽  
Mild Stress ◽  
Hippocampal Function ◽  
Model Group ◽  
Mice Model ◽  
Protein Levels

Objective: To investigate the role of aerobic exercise in inhibiting chronic unpredictable mild stress (CUMS) depressed mice hippocampal inflammatory response and its potential mechanisms. Methods: Fifty-four male eight-week-old C57BL/6 mice were divided as control group (CG) (18 mice) and model group (36 mice). Model group mice were treated with 13 chronic stimulating factors for 28 days to set up the CUMS depression model. Neurobehavioral assessment was performed after modeling. The mice in the model group were randomly divided into the control model group (MG) and the aerobic exercise group (EG), with 18mice in each group. The EG group carried out the adaptive training of the running platform: 10 m/min, 0° slope, and increased by 10 minutes per day for 6 days. The formal training was carried for 8 weeks with 10 m/min speed, 0° slope, 60 min/d, 6 d/Week. After the training, a neurobehavioral assessment was performed, and hippocampus IL-1β and IL-10 protein levels were detected by ELISA. RT–PCR was used to detect the expression of miR-223 and TLR4, MyD88, and NF-κB in the hippocampus. Western blot was used to detect the expression of TLR4 and phosphorylated NF-κBp65 protein in the hippocampus. Results: The hippocampus function of CUMS depression model mice was impaired. The forced swimming and forced tail suspension time were significantly prolonged, and inflammatory factors IL-1β were significantly increased in the hippocampus. Aerobic exercise significantly improves CUMS-depressed mice hippocampal function, effectively reducing depressive behavior and IL-1β levels, and increasing IL-10 levels. Besides, aerobic exercise significantly upregulates the expression level of miR-223 and inhibits the high expression of TLR4, MyD88, and NF-κB. Conclusion: Aerobic exercise significantly increases the CUMS-depressed mice hippocampus expression of miR-223, and inhibits the downstream TLR4/MyD88-NF-κB signaling pathway and the hippocampal inflammatory response, which contributes to the improvement of the hippocampal function.

scholarly journals Panton-Valentine Leucocidin Proves Direct Neuronal Targeting and Its Early Neuronal and Glial Impacts a Rabbit Retinal Explant Model

Toxins ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 455 ◽  
Author(s):  
XuanLi Liu ◽  
Michel J Roux ◽  
Serge Picaud ◽  
Daniel Keller ◽  
Arnaud Sauer ◽  
...  
Keyword(s):  
Cell Activation ◽  
Ganglion Cells ◽  
Glial Activation ◽  
Inflammatory Factors ◽  
In Vivo Model ◽  
Suitable Model ◽  
Dependent Manner ◽  
Retinal Explants ◽  
Glial Changes

: Panton-Valentine leukocidin (PVL) retinal intoxication induces glial activation and inflammatory response via the interaction with retinal neurons. In this study, rabbit retinal explant was used as a model to study neuronal and glial consequences of PVL intoxication. Retinal explants were treated with different concentrations of PVL. PVL location and neuronal and glial changes were examined using immunohistochemistry. Some inflammatory factors were quantified using RT-qPCR at 4 and 8 h. These results were compared with those of control explants. PVL co-localized rapidly with retinal ganglion cells and with horizontal cells. PVL induced Müller and microglial cell activation. Retinal structure was altered and some amacrine and microglial cells underwent apoptosis. Glial activation and cell apoptosis increased in a PVL concentration- and time-dependent manner. IL-6 and IL-8 expression increased in PVL-treated explants but less than in control explants, which may indicate that other factors were responsible for glial activation and retinal apoptosis. On retinal explants, PVL co-localized with neuronal cells and induced glial activation together with microglial apoptosis, which confirms previous results observed in in vivo model. Rabbit retinal explant seems to be suitable model to further study the process of PVL leading to glial activation and retinal cells apoptosis.

scholarly journals Effects of an Aquaporin 4 Inhibitor, TGN-020, on Murine Diabetic Retina

2020 ◽  
Vol 21 (7) ◽  
pp. 2324
Author(s):  
Shou Oosuka ◽  
Teruyo Kida ◽  
Hidehiro Oku ◽  
Taeko Horie ◽  
Seita Morishita ◽  
...  
Keyword(s):  
High Glucose ◽  
Evans Blue ◽  
Müller Cells ◽  
Diabetic Rats ◽  
Aquaporin 4 ◽  
Ros Production ◽  
Muller Cells ◽  
Retinal Edema ◽  
Protein Levels ◽  
Diabetic Retina

Purpose: To investigate the effect of a selective aquaporin 4 (AQP4) inhibitor, 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020), on the expression of vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS) production, as well as on the retinal edema in diabetic retina. Methods: Intravitreal injections of bevacizumab, TGN-020, or phosphate-buffered saline (PBS) were performed on streptozotocin-induced diabetic rats. Retinal sections were immunostained for anti-glial fibrillary acidic protein (GFAP), anti-AQP4, and anti-VEGF. Protein levels of VEGF from collected retinas were determined by Western blot analysis. In addition, retinal vascular leakage of Evans Blue was observed in the flat-mounted retina from the diabetic rats in the presence or absence of TGN-020. Volumetric changes of rat retinal Müller cells (TR-MUL5; transgenic rat Müller cells) and intracellular levels of ROS were determined using flow cytometry analysis of ethidium fluorescence in the presence or absence of TGN-020 or bevacizumab under physiological and high glucose conditions. Results: In the diabetic retina, the immunoreactivity and protein levels of VEGF were suppressed by TGN-020. AQP4 immunoreactivity was higher than in the control retinas and the expressions of AQP4 were co-localized with GFAP. Similarly to VEGF, AQP4 and GFAP were also suppressed by TGN-020. In the Evans Blue assay, TGN-020 decreased leakage in the diabetic retinas. In the cultured Müller cells, the increase in cell volumes and intracellular ROS production under high glucose condition were suppressed by exposure to TGN-020 as much as by exposure to bevacizumab. Conclusion: TGN-020 may have an inhibitory effect on diabetic retinal edema.

Müller Cell Ca2+ Waves Evoked by Purinergic Receptor Agonists in Slices of Rat Retina

2001 ◽  
Vol 85 (2) ◽  
pp. 986-994 ◽  
Author(s):  
Yang Li ◽  
Lynne A. Holtzclaw ◽  
James T. Russell
Keyword(s):  
Glial Cells ◽  
Purinergic Receptor ◽  
Rank Order ◽  
Müller Cells ◽  
Uridine Diphosphate ◽  
Muller Cells ◽  
Wave Amplification ◽  
Dye Loading ◽  
Intracellular Ca ◽  
Retinal Slices

We have measured agonist evoked Ca2+ waves in Müller cells in situ within freshly isolated retinal slices. Using an eye cup dye loading procedure we were able to preferentially fill Müller glial cells in retinal slices with calcium green. Fluorescence microscopy revealed that bath perfusion of slices with purinergic agonists elicits Ca2+ waves in Müller cells, which propagate along their processes. These Ca2+ signals were insensitive to tetrodotoxin (TTX, 1.0 μM) pretreatment. Cells were readily identified as Müller cells by their unique morphology and by subsequent immunocytochemical labeling with glial fibrillary acidic protein antibodies. While cells never exhibited spontaneous Ca2+ oscillations, purinoreceptor agonists, ATP, 2 MeSATP, ADP, 2 MeSADP, and adenosine readily elicited Ca2+ waves. These waves persisted in the absence of [Ca2+]o but were abolished by thapsigargin pretreatment, suggesting that the purinergic agonists tested act by releasing Ca2+ from intracellular Ca2+ stores. The rank order of potency of different purines and pyrimidines for inducing Ca2+ signals was 2 MeSATP = 2MeSADP > ADP > ATP ≫ αβmeATP = uridine triphosphate (UTP) > uridine diphosphate (UDP). The Ca2+signals evoked by ATP, ADP, and 2 MeSATP were inhibited by reactive blue (100 μM) and suramin (200 μM), and the adenosine induced signals were abolished only by 3,7-dimethyl-1-propargylxanthine (200 μM) and not by 1,3-dipropyl-8-(2-amino-4-chlorophenyl)-xanthine) or 8-cyclopentyl-1,3-dipropylxanthine at the same concentration. Based on these pharmacological characteristics and the dose-response relationships for ATP, 2 MeSATP, 2 MeSADP, ADP, and adenosine, we concluded that Müller cells express the P1A2 and P2Y1 subtypes of purinoceptors. Analysis of Ca2+ responses showed that, similar to glial cells in culture, wave propagation occurred by regenerative amplification at specialized Ca2+ release sites (wave amplification sites), where the rate of Ca2+ release was significantly enhanced. These data suggest that Müller cells in the retina may participate in signaling, and this may serve as an extra-neuronal signaling pathway.

scholarly journals Glial cell regulation of neuronal activity and blood flow in the retina by release of gliotransmitters

2015 ◽  
Vol 370 (1672) ◽  
pp. 20140195 ◽  
Author(s):  
Eric A. Newman
Keyword(s):  
Blood Flow ◽  
Arachidonic Acid ◽  
Glial Cells ◽  
Neuronal Activity ◽  
Neurovascular Coupling ◽  
Müller Cells ◽  
Future Research ◽  
Prostaglandin E ◽  
Sk Channels ◽  
Muller Cells

Astrocytes in the brain release transmitters that actively modulate neuronal excitability and synaptic efficacy. Astrocytes also release vasoactive agents that contribute to neurovascular coupling. As reviewed in this article, Müller cells, the principal retinal glial cells, modulate neuronal activity and blood flow in the retina. Stimulated Müller cells release ATP which, following its conversion to adenosine by ectoenzymes, hyperpolarizes retinal ganglion cells by activation of A1 adenosine receptors. This results in the opening of G protein-coupled inwardly rectifying potassium (GIRK) channels and small conductance Ca 2+ -activated K + (SK) channels. Tonic release of ATP also contributes to the generation of tone in the retinal vasculature by activation of P2X receptors on vascular smooth muscle cells. Vascular tone is lost when glial cells are poisoned with the gliotoxin fluorocitrate. The glial release of vasoactive metabolites of arachidonic acid, including prostaglandin E 2 (PGE 2 ) and epoxyeicosatrienoic acids (EETs), contributes to neurovascular coupling in the retina. Neurovascular coupling is reduced when neuronal stimulation of glial cells is interrupted and when the synthesis of arachidonic acid metabolites is blocked. Neurovascular coupling is compromised in diabetic retinopathy owing to the loss of glial-mediated vasodilation. This loss can be reversed by inhibiting inducible nitric oxide synthase. It is likely that future research will reveal additional important functions of the release of transmitters from glial cells.

scholarly journals Hydrogen Sulfide Ameliorates High Glucose-induced Inflammation Through SIRT1-mTOR/NF-κB Signaling Pathway in HT-22 cells

2020 ◽  
Author(s):  
Xinrui Li ◽  
Yinghua Yu ◽  
Peiquan Yu ◽  
Ting Xu ◽  
Jiao Liu ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Inflammatory Response ◽  
Signaling Pathway ◽  
High Glucose ◽  
Near Infrared ◽  
Neuronal Cell ◽  
Inflammatory Factors ◽  
Sodium Hydrosulfide ◽  
Protein Levels

Abstract Background: Hyperglycemia-induced neuroinflammation promotes the progression of diabetic encephalopathy (DE). Hydrogen sulfide (H2S) exerts anti-inflammatory and neuroprotective activities against neurodegenerative diseases. However, its role in hyperglycemia-induced neuronal inflammation has not been investigated. Herein, we examined the effects and its related signaling pathway of H2S on inflammatory response in high glucose-treated HT-22 cells.Methods: A hippocampal neuronal cell line, HT-22, was used as an in vitro model to explore the function of H2S on inflammatory response triggered by high glucose. A dicyanoisophorone-based near-infrared fluorescent probe (NIR-NP) was synthesized to detect H2S levels in HT-22 cells. Western blotting, immunofluorescence and real time-qPCR were carried out to study the mechanism of action for H2S.Results: We found that high glucose (85 mM) decreased the level of endogenous H2S and the expression of cystathionine-β-synthase (CBS) which is the main enzyme for H2S production in the brain. Sodium hydrosulfide (NaHS, a H2S donor) or S-adenosylmethionine (SAMe, an allosteric activator of CBS) administration restored high glucose-induced downregulation of CBS and H2S levels. Importantly, high glucose upregulated the level of pro-inflammatory factors (IL-1β, IL-6, TNF-α) in HT-22 cells. Treatment with NaHS or SAMe alleviated this enhanced transcription of these pro-inflammatory factors, suggesting that H2S might ameliorate high glucose-induced inflammation in HT-22 cells. We also found that high glucose reduced SIRT1 protein levels. SIRT1 reduction elevated the level of p-mTOR, p-NF-κB and pro-inflammatory factors, which were restored by resveratrol (a SIRT1 agonist). These results suggested that SIRT1 might be an upstream mediator of mTOR/NF-κB signaling pathway. Furthermore, NaHS or SAMe treatment reversed the expression of SIRT1, mTOR and NF-κB under high glucose conditions.Conclusions: Our study revealed that high glucose decreased CBS to reduce the production of H2S, which in turn decreased the expression of SIRT1. The reduction of SIRT1 activated mTOR/NF-κB signaling to promote inflammation. Given that promoting H2S production using NaHS or SAMe can reverse high glucose-induced inflammatory response, our study might shed light on the prophylactic treatment of DE.

scholarly journals Effects of Adult Müller Cells and Their Conditioned Media on the Survival of Stem Cell-Derived Retinal Ganglion Cells

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1759
Author(s):  
Xandra Pereiro ◽  
Adam M. Miltner ◽  
Anna La Torre ◽  
Elena Vecino
Keyword(s):  
Stem Cell ◽  
Cell Survival ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Müller Cells ◽  
Cell Types ◽  
Conditioned Media ◽  
Retinal Ganglion ◽  
Muller Cells ◽  
Müller Glia

Retinal neurons, particularly retinal ganglion cells (RGCs), are susceptible to the degenerative damage caused by different inherited conditions and environmental insults, leading to irreversible vision loss and, ultimately, blindness. Numerous strategies are being tested in different models of degeneration to restore vision and, in recent years, stem cell technologies have offered novel avenues to obtain donor cells for replacement therapies. To date, stem cell–based transplantation in the retina has been attempted as treatment for photoreceptor degeneration, but the same tools could potentially be applied to other retinal cell types, including RGCs. However, RGC-like cells are not an abundant cell type in stem cell–derived cultures and, often, these cells degenerate over time in vitro. To overcome this limitation, we have taken advantage of the neuroprotective properties of Müller glia (one of the main glial cell types in the retina) and we have examined whether Müller glia and the factors they secrete could promote RGC-like cell survival in organoid cultures. Accordingly, stem cell-derived RGC-like cells were co-cultured with adult Müller cells or Müller cell-conditioned media was added to the cultures. Remarkably, RGC-like cell survival was substantially enhanced in both culture conditions, and we also observed a significant increase in their neurite length. Interestingly, Atoh7, a transcription factor required for RGC development, was up-regulated in stem cell-derived organoids exposed to conditioned media, suggesting that Müller cells may also enhance the survival of retinal progenitors and/or postmitotic precursor cells. In conclusion, Müller cells and the factors they release promote organoid-derived RGC-like cell survival, neuritogenesis, and possibly neuronal maturation.

Sign in / Sign up

Export Citation Format

Share Document