Tumor necrosis factor and nitric oxide production by retinal M�ller glial cells from rats exhibiting inherited retinal dystrophy

Cotinet, Aline; Goureau, Olivier; Hicks, David; Thillaye-Goldenberg, B.; Kozak, Y. de

doi:10.1002/(sici)1098-1136(199705)20:1<59::aid-glia6>3.0.co;2-0

Cited by 36 publications

(4 citation statements)

References 50 publications

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“…These effects are likely mediated in response to inflammatory mediators from activated microglia such as IFN-γ, IL-1β, and TNF-α as described in previous reports [45-48]. This production of inflammatory mediators in response to signals from activated microglia suggests that Müller cells may be able to amplify inflammatory responses in the retina in a positive feedback loop.…”

Section: Discussionsupporting

confidence: 58%

Adaptive Müller cell responses to microglial activation mediate neuroprotection and coordinate inflammation in the retina

Wang

Zhao

et al. 2011

J Neuroinflammation

197

184

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PurposeMicroglia and Müller cells are prominent participants in retinal responses to injury and disease that shape eventual tissue adaptation or damage. This investigation examined how microglia and Müller cells interact with each other following initial microglial activation.MethodsMouse Müller cells were cultured alone, or co-cultured with activated or unactivated retinal microglia, and their morphological, molecular, and functional responses were evaluated. Müller cell-feedback signaling to microglia was studied using Müller cell-conditioned media. Corroborative in vivo analyses of retinal microglia-Müller cell interactions in the mouse retina were also performed.ResultsOur results demonstrate that Müller cells exposed to activated microglia, relative to those cultured alone or with unactivated microglia, exhibit marked alterations in cell morphology and gene expression that differed from those seen in chronic gliosis. These Müller cells demonstrated in vitro (1) an upregulation of growth factors such as GDNF and LIF, and provide neuroprotection to photoreceptor cells, (2) increased pro-inflammatory factor production, which in turn increased microglial activation in a positive feedback loop, and (3) upregulated chemokine and adhesion protein expression, which allowed Müller cells to attract and adhere to microglia. In vivo activation of microglia by intravitreal injection of lipopolysaccharide (LPS) also induced increased Müller cell-microglia adhesion, indicating that activated microglia may translocate intraretinally in a radial direction using Müller cell processes as an adhesive scaffold.ConclusionOur findings demonstrate that activated microglia are able to influence Müller cells directly, and initiate a program of bidirectional microglia-Müller cell signaling that can mediate adaptive responses within the retina following injury. In the acute aftermath following initial microglia activation, Müller cell responses may serve to augment initial inflammatory responses across retinal lamina and to guide the intraretinal mobilization of migratory microglia using chemotactic cues and adhesive cell contacts. Understanding adaptive microglia-Müller cell interactions in injury responses can help discover therapeutic cellular targets for intervention in retinal disease.

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Section: Discussionsupporting

confidence: 58%

Adaptive Müller cell responses to microglial activation mediate neuroprotection and coordinate inflammation in the retina

Wang

Zhao

et al. 2011

J Neuroinflammation

197

184

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“…33,36,37 Chronic activation of glial cells can also trigger the inflammatory cascade, increase vascular permeability, and disrupt the blood retinal/brain barrier. 33,38–40 Activation also alters water and ion buffering capabilities of Müller cells. 33,41–43 Subretinal glial membranes may create an unhealthy environment for surviving photoreceptor cells and RPE cells.…”

Section: Discussionmentioning

confidence: 99%

Subretinal Glial Membranes in Eyes With Geographic Atrophy

Edwards

McLeod

Bhutto

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeMüller cells create the external limiting membrane (ELM) by forming junctions with photoreceptor cells. This study evaluated the relationship between focal photoreceptors and RPE loss in geographic atrophy (GA) and Müller cell extension into the subretinal space.MethodsHuman donor eyes with no retinal disease or geographic atrophy (GA) were fixed and the eye cups imaged. The retinal posterior pole was stained for glial fibrillary acidic protein (GFAP; astrocytes and activated Müller cells) and vimentin (Müller cells) while the submacular choroids were labeled with Ulex Europaeus Agglutinin lectin (blood vessels). Choroids and retinas were imaged using a Zeiss 710 confocal microscope. Additional eyes were cryopreserved or processed for transmission electron microscopy (TEM) to better visualize the Müller cells.ResultsVimentin staining of aged control retinas (n = 4) revealed a panretinal cobblestone-like ELM. While this pattern was also observed in the GA retinas (n = 7), each also had a distinct area in which vimentin+ and vimentin+/GFAP+ processes created a subretinal membrane. Subretinal glial membranes closely matched areas of RPE atrophy in the gross photos. Choroidal vascular loss was also evident in these atrophic areas. Smaller glial projections were noted, which correlated with drusen in gross photos. The presence of glia in the subretinal space was confirmed by TEM and cross cross-section immunohistochemistry.ConclusionsIn eyes with GA, subretinal Müller cell membranes present in areas of RPE atrophy may be a Müller cell attempt to replace the ELM. These membranes could interfere with treatments such as stem cell therapy.

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“…We observed in our analysis that RNA levels of Ifn-γ , Il-6 , Vegf , and Thbs1 to be greater following Müller glia activation. Previously, Cotinet et.al and Goureau showed that IFN-γ can trigger Müller glia to regulate TNF-α and nitric oxide (NO) [101, 102]. Similarly, IL-6 has been shown to induce Müller glia-derived progenitor cells in the injured zebrafish and chick retina [40, 103].…”

Section: Discussionmentioning

confidence: 99%

Microglia activation is essential for BMP7-mediated retinal reactive gliosis

Dharmarajan

Fisk

Sorenson

et al. 2017

J Neuroinflammation

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BackgroundOur previous studies have shown that BMP7 is able to trigger activation of retinal macroglia. However, these studies showed the responsiveness of Müller glial cells and retinal astrocytes in vitro was attenuated in comparison to those in vivo, indicating other retinal cell types may be mediating the response of the macroglial cells to BMP7. In this study, we test the hypothesis that BMP7-mediated gliosis is the result of inflammatory signaling from retinal microglia.MethodsAdult mice were injected intravitreally with BMP7 and eyes harvested 1, 3, or 7 days postinjection. Some mice were treated with PLX5622 (PLX) to ablate microglia and were subsequently injected with control or BMP7. Processed tissue was analyzed via immunofluorescence, RT-qPCR, or ELISA. In addition, cultures of retinal microglia were treated with vehicle, lipopolysaccharide, or BMP7 to determine the effects of BMP7-isolated cells.ResultsMice injected with BMP7 showed regulation of various inflammatory markers at the RNA level, as well as changes in microglial morphology. Isolated retinal microglia also showed an upregulation of BMP-signaling components following treatment. In vitro treatment of retinal astrocytes with conditioned media from activated microglia upregulated RNA levels of gliosis markers. In the absence of microglia, the mouse retina showed a subdued gliosis and inflammatory response when exposed to BMP7.ConclusionsGliosis resulting from BMP7 is mediated through an inflammatory response from retinal microglia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0855-0) contains supplementary material, which is available to authorized users.

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Tumor necrosis factor and nitric oxide production by retinal M�ller glial cells from rats exhibiting inherited retinal dystrophy

Cited by 36 publications

References 50 publications

Adaptive Müller cell responses to microglial activation mediate neuroprotection and coordinate inflammation in the retina

Adaptive Müller cell responses to microglial activation mediate neuroprotection and coordinate inflammation in the retina

Subretinal Glial Membranes in Eyes With Geographic Atrophy

Microglia activation is essential for BMP7-mediated retinal reactive gliosis

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