IOP induces upregulation of GFAP and MHC-II and microglia reactivity in mice retina contralateral to experimental glaucoma

Gallego, Beatriz; Salazar, Juan J.; Hoz, Rosa de; Rojas, Blanca; Ramírez, Ana I.; Salinas‐Navarro, Manuel; Ortín-Martínez, Arturo; Valiente‐Soriano, Francisco J.; Avilés‐Trigueros, Marcelino; Villegas‐Pérez, María Paz; Vidal‐Sanz, Manuel; Triviño, Alberto

doi:10.1186/1742-2094-9-92

Cited by 202 publications

(239 citation statements)

References 74 publications

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“…Eight weeks after microbead injection we observed a significant reduction in the number of SMI32-positive RGC somata and dendrites ( Figure 3, E and F). Blockade of GJs with MFA again provided significant protection to microbead-injected retinas as indicated by sion in astrocytes and Müller cells in retina (27,28). Under control conditions, GFAP immunofluorescence was confined exclusively to astrocytes in the GCL, with no detectable immunolabeling in the IPL, INL, or OPL ( Figure 2A).…”

Section: Cx36mentioning

confidence: 90%

Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma

Akopian¹,

Kumar²,

Ramakrishnan³

et al. 2017

Journal of Clinical Investigation

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The progressive death of retinal ganglion cells and resulting visual deficits are hallmarks of glaucoma, but the underlying mechanisms remain unclear. In many neurodegenerative diseases, cell death induced by primary insult is followed by a wave of secondary loss. Gap junctions (GJs), intercellular channels composed of subunit connexins, can play a major role in secondary cell death by forming conduits through which toxic molecules from dying cells pass to and injure coupled neighbors. Here we have shown that pharmacological blockade of GJs or genetic ablation of connexin 36 (Cx36) subunits, which are highly expressed by retinal neurons, markedly reduced loss of neurons and optic nerve axons in a mouse model of glaucoma. Further, functional parameters that are negatively affected in glaucoma, including the electroretinogram, visual evoked potential, visual spatial acuity, and contrast sensitivity, were maintained at control levels when Cx36 was ablated. Neuronal GJs may thus represent potential therapeutic targets to prevent the progressive neurodegeneration and visual impairment associated with glaucoma.

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Section: Cx36mentioning

confidence: 90%

Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma

Akopian¹,

Kumar²,

Ramakrishnan³

et al. 2017

Journal of Clinical Investigation

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“…Perfuse intact, non-operated mice as described in 4.1 and use them as uninjured controls. The use of contralateral eyes from operated mice is not recommended to assess RGC survival because changes in contralateral eyes following injury have been reported 15,16 and can confound data interpretation. Alternatively, use sham-operated eyes injected with 1.5 µl of BSS as controls.…”

Section: Assessment Of Retinal Ganglion Cell Soma and Axon Survivalmentioning

confidence: 99%

A Magnetic Microbead Occlusion Model to Induce Ocular Hypertension-Dependent Glaucoma in Mice

Itō

Belforte

Vargas

et al. 2016

JoVE

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The use of rodent models of glaucoma has been essential to understand the molecular mechanisms that underlie the pathophysiology of this multifactorial neurodegenerative disease. With the advent of numerous transgenic mouse lines, there is increasing interest in inducible murine models of ocular hypertension. Here, we present an occlusion model of glaucoma based on the injection of magnetic microbeads into the anterior chamber of the eye using a modified microneedle with a facetted bevel. The magnetic microbeads are attracted to the iridocorneal angle using a handheld magnet to block the drainage of aqueous humour from the anterior chamber. This disruption in aqueous dynamics results in a steady elevation of intraocular pressure, which subsequently leads to the loss of retinal ganglion cells, as observed in human glaucoma patients. The microbead occlusion model presented in this manuscript is simple compared to other inducible models of glaucoma and also highly effective and reproducible. Importantly, the modifications presented here minimize common issues that often arise in occlusion models. First, the use of a bevelled glass microneedle prevents backflow of microbeads and ensures that minimal damage occurs to the cornea during the injection, thus reducing injury-related effects. Second, the use of magnetic microbeads ensures the ability to attract most beads to the iridocorneal angle, effectively reducing the number of beads floating in the anterior chamber avoiding contact with other structures (e.g., iris, lens). Lastly, the use of a handheld magnet allows flexibility when handling the small mouse eye to efficiently direct the magnetic microbeads and ensure that there is little reflux of the microbeads from the eye when the microneedle is withdrawn. In summary, the microbead occlusion mouse model presented here is a powerful investigative tool to study neurodegenerative changes that occur during the onset and progression of glaucoma.

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“…As a general measure of glial reactivity, we examined immunolabeling intensity of the astrocyte marker GFAP and the Müller glia marker glutamine synthetase. An increase in the expression of these markers is associated with increased reactivity or activation of astrocytes and Müller glia in response to a variety of stressors in retina [37][38][39][40][41][42][43][44]. Since we evaluated overall labeling intensity, increases in GFAP or glutamine synthetase levels can be attributed to either increased expression on a per cell basis, which accompanies hypertrophy, or an increase in density.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies indicate that uptake and anterograde transport of CTB by RGCs is an early indicator of RGC decline [34][35][36]. Similarly, expression of GFAP by astrocytes and glutamine synthetase by Müller cells is altered in response to retinal damage, including glaucoma [37][38][39][40][41][42][43][44]. For our analysis in whole mount retina, we sampled 60x fields in the area between mid-central and mid-peripheral retina.…”

Section: Stressor-dependent Changes In Gp130 Are Accompanied By Altermentioning

confidence: 99%

Stressor-dependent Alterations in Glycoprotein 130: Implications for Glial Cell Reactivity, Cytokine Signaling and Ganglion Cell Health in Glaucoma

Echevarria

et al. 2013

J Clin Exp Ophthalmol

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Objective: The interleukin-6 (IL-6) family of cytokines is associated with retinal ganglion cell (RGC) survival and glial reactivity in glaucoma. The purpose of this study was to evaluate glaucoma-related changes in glycoprotein-130 (gp130), the common signal transducer of the IL-6 family of cytokines, as they relate to RGC health, glial reactivity and expression of IL-6 cytokine family members. Methods:For all experiments, we examined healthy retina (young C57), aged retina (aged C57), retina predisposed to glaucoma (young DBA/2) and retina with IOP-induced glaucoma (aged DBA/2). We determined retinal gene expression of gp130 and IL-6 family members, using quantitative PCR, and protein expression of gp130, using multiplex ELISA. For protein localization and cell-specific expression, we performed co-immunolabeling for gp130 and cell type-specific markers. We used quantitative microscopy to measure layer-specific expression of gp130 and its relationships to astrocyte and Müller glia reactivity and RGC axonal transport, as determined by uptake and transport of cholera toxin β-subunit (CTB).Results: Gene expression of gp130 was elevated with all glaucoma-related stressors, but only normal aging increased protein levels. In healthy retina, gp130 localized primarily to the inner retina, where it was expressed by astrocytes, Müller cells and RGCs. Layer-specific analysis of gp130 expression revealed increased expression in aging retina and decreased expression in glaucomatous retina that was eccentricity-dependent. These glaucoma-related changes in gp130 expression correlated with the level of GFAP and glutamine synthetase expression, as well as axonal transport in RGCs. The relationships between gp130, glial reactivity and RGC health could impact signaling by many IL-6 family cytokines, which exhibited overall increased expression in a stressor-dependent manner.Conclusions: Glaucoma-related stressors, including normal aging, glaucoma predisposition and IOP-induced glaucoma, differentially alter expression of gp130 and these alterations have direct implications for astrocyte and Müller glia reactivity, RGC health and cytokine signaling.

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IOP induces upregulation of GFAP and MHC-II and microglia reactivity in mice retina contralateral to experimental glaucoma

Cited by 202 publications

References 74 publications

Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma

Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma

A Magnetic Microbead Occlusion Model to Induce Ocular Hypertension-Dependent Glaucoma in Mice

Stressor-dependent Alterations in Glycoprotein 130: Implications for Glial Cell Reactivity, Cytokine Signaling and Ganglion Cell Health in Glaucoma

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