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Biochimica Et Biophysica Acta.... Dec 2021Chronic low-grade retinal inflammation is an essential contributor to the pathogenesis of diabetic retinopathy (DR). It is characterized by increased retinal cell...
Chronic low-grade retinal inflammation is an essential contributor to the pathogenesis of diabetic retinopathy (DR). It is characterized by increased retinal cell expression and secretion of a variety of inflammatory cytokines; among these, IL-1β has the reputation of being a major driver of cytokine-induced inflammation. IL-1β and other cytokines drive inflammatory changes that cause damage to retinal cells, leading to the hallmark vascular lesions of DR; these include increased leukocyte adherence, vascular permeability, and capillary cell death. Nuclear factor of activated T-cells (NFAT) is a transcriptional regulator of inflammatory cytokines and adhesion molecules and is expressed in retinal cells. Consequently, it may influence multiple pathogenic steps early in DR. We investigated the NFAT-dependency of IL-1β-induced inflammation in human Müller cells (hMC) and human retinal microvascular endothelial cells (hRMEC). Our results show that an NFAT inhibitor, Inhibitor of NFAT-Calcineurin Association-6 (INCA-6), decreased IL-1β-induced expression of IL-1β and TNFα in hMC, while having no effect on VEGF, CCL2, or CCL5 expression. We also demonstrate that INCA-6 attenuated IL-1β-induced increases of IL-1β, TNFα, IL-6, CCL2, and CCL5 (inflammatory cytokines and chemokines), and ICAM-1 and E-selectin (leukocyte adhesion molecules) expression in hRMEC. INCA-6 similarly inhibited IL-1β-induced increases in leukocyte adhesion in both hRMEC monolayers in vitro and an acute model of retinal inflammation in vivo. Finally, INCA-6 rescued IL-1β-induced permeability in both hRMEC monolayers in vitro and an acute model of retinal inflammation in vivo. Taken together, these data demonstrate the potential of NFAT inhibition to mitigate retinal inflammation secondary to diabetes.
Topics: Calcineurin Inhibitors; Cells, Cultured; Chemokine CCL2; Chemokine CCL5; Diabetic Retinopathy; E-Selectin; Endothelial Cells; Ependymoglial Cells; Gene Expression Regulation; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-1beta; NFATC Transcription Factors; Retina; Retinal Vasculitis; Retinal Vessels; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A
PubMed: 34343639
DOI: 10.1016/j.bbadis.2021.166238 -
Philosophical Transactions of the Royal... Jul 2015Astrocytes in the brain release transmitters that actively modulate neuronal excitability and synaptic efficacy. Astrocytes also release vasoactive agents that... (Review)
Review
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 E2 (PGE2) 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.
Topics: Action Potentials; Ependymoglial Cells; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Humans; Neurotransmitter Agents; Regional Blood Flow; Retinal Neurons; Retinal Vessels; Small-Conductance Calcium-Activated Potassium Channels
PubMed: 26009774
DOI: 10.1098/rstb.2014.0195 -
The Proceedings of the Nutrition Society Aug 2019Animal models are valuable for the study of complex behaviours and physiology such as the control of appetite because genetic, pharmacological and surgical approaches... (Review)
Review
Animal models are valuable for the study of complex behaviours and physiology such as the control of appetite because genetic, pharmacological and surgical approaches allow the investigation of underlying mechanisms. However, the majority of such studies are carried out in just two species, laboratory mice and rats. These conventional laboratory species have been intensely selected for high growth rate and fecundity, and have a high metabolic rate and short lifespan. These aspects limit their translational relevance for human appetite control. This review will consider the value of studies carried out in a seasonal species, the Siberian hamster, which shows natural photoperiod-regulated annual cycles in appetite, growth and fattening. Such studies reveal that this long-term control is not simply an adjustment of the known hypothalamic neuronal systems that control hunger and satiety in the short term. Long-term cyclicity is probably driven by hypothalamic tanycytes, glial cells that line the ventricular walls of the hypothalamus. These unique cells sense nutrients and metabolic hormones, integrate seasonal signals and effect plasticity of surrounding neural circuits through their function as a stem cell niche in the adult. Studies of glial cell function in the hypothalamus offer new potential for identifying central targets for appetite and body weight control amenable to dietary or pharmacological manipulation.
Topics: Animals; Appetite; Body Weight; Energy Intake; Energy Metabolism; Ependymoglial Cells; Female; Hormones; Hypothalamus; Male; Mice; Phodopus; Photoperiod; Rats
PubMed: 30457065
DOI: 10.1017/S0029665118002665 -
Ophthalmic & Physiological Optics : the... Nov 2020To investigate presumed activated retinal astrocytes and Müller cells (ARAM) detected by scanning laser ophthalmoscopy (SLO) and spectral domain optical coherence...
PURPOSE
To investigate presumed activated retinal astrocytes and Müller cells (ARAM) detected by scanning laser ophthalmoscopy (SLO) and spectral domain optical coherence tomography, and to investigate its presence in healthy controls as well as its relationship to posterior vitreal detachment (PVD) and glaucoma.
METHODS
This retrospective study involved 1337 eyes of 805 controls between ages 8 and 90, and 250 eyes of 146 patients with glaucoma between the ages of 28 and 95. Subjects were counted as possessing ARAM only if they met the following criteria: (1) a patchy, discrete, glittering appearance on SLO, (2) a distinct, flat, hyper-reflective layer at the internal limiting membrane on at least one B-scan crossing the glittering area and (3) absence of any surface wrinkling retinopathy. The diagnosis of PVD was based on both the patient's clinical examination and imaging data. Frequency tables were used to describe categorical variables and differences were compared by means of χ . Analyses were separated based on right and left eye, first on controls and then between glaucomatous eyes and age-similar sex-matched controls.
RESULTS
ARAM was found in both healthy controls and patients with glaucoma at similar frequencies. There was no association between having glaucoma and the presence of ARAM. ARAM was not different between the sexes but was associated with age and having a PVD.
CONCLUSIONS
This large retrospective study found that ARAM can be seen in healthy controls, is associated with PVD and possibly independently with age, and occurred at similar frequency in glaucomatous eyes.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Astrocytes; Child; Ependymoglial Cells; Female; Glaucoma, Open-Angle; Humans; Male; Middle Aged; Ophthalmoscopy; Retina; Retrospective Studies; Tomography, Optical Coherence; Young Adult
PubMed: 32885879
DOI: 10.1111/opo.12731 -
PloS One 2021Diabetic retinopathy (DR), the most common complication of diabetes mellitus, is associated with oxidative stress, nuclear factor-κB (NFκB) activation, and excess...
Diabetic retinopathy (DR), the most common complication of diabetes mellitus, is associated with oxidative stress, nuclear factor-κB (NFκB) activation, and excess production of vascular endothelial growth factor (VEGF) and intracellular adhesion molecule-1 (ICAM-1). Muller glial cells, spanning the entirety of the retina, are involved in DR inflammation. Mitigation of DR pathology currently occurs via invasive, frequently ineffective therapies which can cause adverse effects. The application of far-red to near-infrared (NIR) light (630-1000nm) reduces oxidative stress and inflammation in vitro and in vivo. Thus, we hypothesize that 670nm light treatment will diminish oxidative stress preventing downstream inflammatory mechanisms associated with DR initiated by Muller cells. In this study, we used an in vitro model system of rat Müller glial cells grown under normal (5 mM) or high (25 mM) glucose conditions and treated with a 670 nm light emitting diode array (LED) (4.5 J/cm2) or no light (sham) daily. We report that a single 670 nm light treatment diminished reactive oxygen species (ROS) production and preserved mitochondrial integrity in this in vitro model of early DR. Furthermore, treatment for 3 days in culture reduced NFκB activity to levels observed in normal glucose and prevented the subsequent increase in ICAM-1. The ability of 670nm light treatment to prevent early molecular changes in this in vitro high glucose model system suggests light treatment could mitigate early deleterious effects modulating inflammatory signaling and diminishing oxidative stress.
Topics: Animals; Cells, Cultured; Energy Metabolism; Ependymoglial Cells; Glucose; Infrared Rays; Mitochondria; Oxidative Stress; Rats; Reactive Oxygen Species; Sweetening Agents
PubMed: 34860856
DOI: 10.1371/journal.pone.0260968 -
Proceedings. Biological Sciences Jul 2017Bilaterians usually possess a central nervous system, composed of neurons and supportive cells called glial cells. Whereas neuronal cells are highly comparable in all...
Bilaterians usually possess a central nervous system, composed of neurons and supportive cells called glial cells. Whereas neuronal cells are highly comparable in all these animals, glial cells apparently differ, and in deuterostomes, radial glial cells are found. These particular secretory glial cells may represent the archetype of all (macro) glial cells and have not been reported from protostomes so far. This has caused controversial discussions of whether glial cells represent a homologous bilaterian characteristic or whether they (and thus, centralized nervous systems) evolved convergently in the two main clades of bilaterians. By using histology, transmission electron microscopy, immunolabelling and whole-mount hybridization, we show here that protostomes also possess radial glia-like cells, which are very likely to be homologous to those of deuterostomes. Moreover, our antibody staining indicates that the secretory character of radial glial cells is maintained throughout their various evolutionary adaptations. This implies an early evolution of radial glial cells in the last common ancestor of Protostomia and Deuterostomia. Furthermore, it suggests that an intraepidermal nervous system-composed of sensory cells, neurons and radial glial cells-was probably the plesiomorphic condition in the bilaterian ancestor.
Topics: Animals; Biological Evolution; Central Nervous System; Ependymoglial Cells; Neuroglia; Neurons
PubMed: 28724733
DOI: 10.1098/rspb.2017.0743 -
Experimental Eye Research Sep 2016Although retinal neurodegenerative conditions such as age-related macular degeneration, glaucoma, diabetic retinopathy, retinitis pigmentosa, and retinal detachment have... (Review)
Review
Although retinal neurodegenerative conditions such as age-related macular degeneration, glaucoma, diabetic retinopathy, retinitis pigmentosa, and retinal detachment have different etiologies and pathological characteristics, they also have many responses in common at the cellular level, including neural and glial remodeling. Structural changes in Müller cells, the large radial glia of the retina in retinal disease and injury have been well described, that of the retinal astrocytes remains less so. Using modern imaging technology to describe the structural remodeling of retinal astrocytes after retinal detachment is the focus of this paper. We present both a review of critical literature as well as novel work focusing on the responses of astrocytes following rhegmatogenous and serous retinal detachment. The mouse presents a convenient model system in which to study astrocyte reactivity since the Mϋller cell response is muted in comparison to other species thereby allowing better visualization of the astrocytes. We also show data from rat, cat, squirrel, and human retina demonstrating similarities and differences across species. Our data from immunolabeling and dye-filling experiments demonstrate previously undescribed morphological characteristics of normal astrocytes and changes induced by detachment. Astrocytes not only upregulate GFAP, but structurally remodel, becoming increasingly irregular in appearance, and often penetrating deep into neural retina. Understanding these responses, their consequences, and what drives them may prove to be an important component in improving visual outcome in a variety of therapeutic situations. Our data further supports the concept that astrocytes are important players in the retina's overall response to injury and disease.
Topics: Animals; Astrocytes; Cats; Cell Plasticity; Disease Models, Animal; Ependymoglial Cells; Humans; Mice; Mice, Mutant Strains; Rats; Rats, Long-Evans; Retinal Detachment; Retinal Ganglion Cells; Sciuridae
PubMed: 27060374
DOI: 10.1016/j.exer.2016.03.027 -
Scientific Reports Oct 2022Interleukin-6 (IL-6) is implicated in various retinal and vascular complications associated with diabetic retinopathy (DR). This cytokine functions through two main...
Interleukin-6 (IL-6) is implicated in various retinal and vascular complications associated with diabetic retinopathy (DR). This cytokine functions through two main modalities: classical signaling, in cells expressing the membrane-bound receptor (IL-6Rα); and trans-signaling, possible in most cells through a soluble form of the receptor (sIL-6R). These pathways are considered to be anti-inflammatory and pro-inflammatory, respectively. Our recent studies in retinal endothelial cells and diabetic mice have shown that inhibiting only IL-6 trans-signaling is sufficient to prevent increased vascular leakage, oxidative stress, and inflammation characteristic of DR. Isolating the specific effects of each signaling pathway, however, remains difficult in cells expressing IL-6Rα that are thus capable of both classical and trans-signaling. Müller glial cells (MGCs), the most abundant retinal macroglial cells, span the entire retinal thickness with vital roles in maintaining retinal homeostasis and regulating the blood-retinal barrier through secreted factors. The specific effects of IL-6 trans-signaling in MGCs remain poorly understood given their responsiveness to both IL-6 signaling modalities. In this study, we addressed these concerns by generating an MGC-specific knockout mouse using Cre-loxP deletion of the Il6ra cytokine-binding region. We assessed transcriptional and translational Il6ra expression to confirm the knockout and characterized the effects of knockout on visual functioning in these mice.
Topics: Mice; Animals; Ependymoglial Cells; Interleukin-6; Mice, Knockout; Endothelial Cells; Diabetes Mellitus, Experimental; Retina; Diabetic Retinopathy; Signal Transduction; Cytokines
PubMed: 36271280
DOI: 10.1038/s41598-022-22329-3 -
International Journal of Molecular... Jun 2023The disorganization of retinal inner layers (DRIL) is an optical coherence tomography (OCT) biomarker strictly associated with visual outcomes in patients with diabetic... (Observational Study)
Observational Study
The disorganization of retinal inner layers (DRIL) is an optical coherence tomography (OCT) biomarker strictly associated with visual outcomes in patients with diabetic macular edema (DME) whose pathophysiology is still unclear. The aim of this study was to characterize in vivo, using retinal imaging and liquid biopsy, DRIL in eyes with DME. This was an observational cross-sectional study. Patients affected by center-involved DME were enrolled. All patients underwent spectral domain optical coherence tomography (SD-OCT) and proteomic analysis of aqueous humor (AH). The presence of DRIL at OCT was analyzed by two masked retinal experts. Fifty-seven biochemical biomarkers were analyzed from AH samples. Nineteen eyes of nineteen DME patients were enrolled. DRIL was present in 10 patients (52.63%). No statistically significant difference was found between DME eyes with and without DRIL, considering the AH concentration of all the analyzed biomarkers except for glial fibrillary acidic protein (GFAP), a biomarker of Müller cells dysfunction ( = 0.02). In conclusion, DRIL, in DME eyes, seems to strictly depend on a major dysfunction of Müller cells, explaining its role not only as imaging biomarker, but also as visual function Müller cells-related parameter.
Topics: Humans; Macular Edema; Diabetic Retinopathy; Cross-Sectional Studies; Ependymoglial Cells; Proteomics; Retrospective Studies; Visual Acuity; Fluorescein Angiography; Retina; Tomography, Optical Coherence; Biomarkers; Diabetes Mellitus
PubMed: 37298558
DOI: 10.3390/ijms24119607 -
Experimental Eye Research Mar 2022Zebrafish possess the ability to completely regenerate the retina following injury, however little is understood about the damage signals that contribute to inducing...
Zebrafish possess the ability to completely regenerate the retina following injury, however little is understood about the damage signals that contribute to inducing Müller glia reprogramming and proliferation to regenerate lost neurons. Multiple studies demonstrated that iron contributes to various retinal injuries, however no link has been shown between iron and zebrafish retinal regeneration. Here we demonstrate that Müller glia exhibit transcriptional changes following injury to regulate iron levels within the retina, allowing for increased iron uptake and decreased export. The response of the zebrafish retina to intravitreal iron injection was then characterized, showing that ferrous, and not ferric, iron induces retinal cell death. Additionally, iron chelation resulted in decreased numbers of TUNEL-positive photoreceptors and fewer proliferating Müller glia. Despite the contribution of iron to retinal cell death, inhibition of ferroptosis did not significantly reduce cell death following light treatment. Finally, we demonstrate that both the anti-ferroptotic protein Glutathione peroxidase 4b and the Transferrin receptor 1b are required for Müller glia proliferation following light damage. Together these findings show that iron contributes to cell death in the light-damaged retina and is essential for inducing the Müller glia regeneration response.
Topics: Animals; Animals, Genetically Modified; Apoptosis; Cell Proliferation; Deferiprone; Ependymoglial Cells; Ferrous Compounds; In Situ Nick-End Labeling; Intravitreal Injections; Light; Phospholipid Hydroperoxide Glutathione Peroxidase; Photoreceptor Cells; Radiation Injuries, Experimental; Receptors, Transferrin; Retinal Degeneration; Zebrafish; Zebrafish Proteins
PubMed: 35074344
DOI: 10.1016/j.exer.2022.108947