Müller Cell–Microglia Cross Talk Drives Neuroinflammation in Diabetic Retinopathy

Abcouwer, Steve F.

doi:10.2337/dbi16-0047

Cited by 53 publications

(47 citation statements)

References 18 publications

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“…PDR is primarily considered microangiopathy and neovascularization disease, but several reactive changes in Müller cells and activation of the resident or migrating macrophages/microglial cells have been reported in the disease pathogenesis 33 . We found a massive upregulation of GFAP stained macroglial cells throughout the Akimba retina (Fig.…”

Section: Resultsmentioning

confidence: 99%

The NLRP3 Inflammasome May Contribute to Pathologic Neovascularization in the Advanced Stages of Diabetic Retinopathy

Chaurasia

Lim

Parikh

et al. 2018

Sci Rep

119

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Diabetic retinopathy (DR) is a retinal microvascular disease characterized by inflammatory and angiogenic pathways. In this study, we evaluated NLRP3 inflammasome in a double transgenic mouse model, Akimba (Ins2AkitaxVEGF+/−), which demonstrates hyperglycemia, vascular hyperpermeability and neovascularization seen in the proliferative DR. Retinal structural integrity, vascular leakage and function were examined by fundus photography, fluorescein angiography, optical coherence tomography, retinal flat mounts, laser speckle flowgraphy (LSFG), and electroretinography in Akimba and its parental strains, Akita (Ins2Akita) and Kimba (trVEGF029) mice. Inflammatory mechanisms involving NLRP3 inflammasome were investigated using real time-PCR, immunohistochemistry, ELISA and western blots. We observed an increased vascular leakage, reduced retinal thickness, and function in Akimba retina. Also, Akimba retina depicts decreased relative flow volume measured by LSFG. Most importantly, high levels of IL-1β along with increased NLRP3, ASC, and Caspase-1 at mRNA and protein levels were observed in Akimba retina. However, the in vivo functional role remains undefined. In conclusion, increased activation of macroglia (GFAP), microglia (Iba-1 and OX-42) and perivascular macrophages (F4/80 and CD14) together with pro-inflammatory (IL-1β and IL-6) and pro-angiogenic markers (PECAM-1, ICAM-1, VEGF, Flt-1, and Flk-1), suggested a critical role for NLRP3 inflammasome in the Akimba mouse model depicting advanced stages of DR pathogenesis.

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Section: Resultsmentioning

confidence: 99%

The NLRP3 Inflammasome May Contribute to Pathologic Neovascularization in the Advanced Stages of Diabetic Retinopathy

Chaurasia

Lim

Parikh

et al. 2018

Sci Rep

119

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“…Microglia‐Müller glia crosstalk has been implicated in retinal degeneration and neuroprotection (Abcouwer, ; Arroba, Alvarez‐Lindo, van Rooijen, & de la Rosa, ; Wang, 2011). We have previously shown that Norgestrel dampens harmful microglial activity that would otherwise lead to photoreceptor cell death (Roche, Wyse‐Jackson, Gomez‐Vicente, et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

“…Alleviating harmful microglial activity promotes photoreceptor survival, by dampening the release of inflammatory factors and reducing phagocytosis (Liang et al, ; Roche, Wyse‐Jackson, Gomez‐Vicente et al, 2016; Roche et al, ; Zabel et al, ; Zhao et al, ). Microglia ‐ Müller glia crosstalk has been implicated in retinal degeneration (Abcouwer, ) and neuroprotection (Arroba et al, ; Wang et al, ). Indeed, we observed a strong temporal correlation between microglial activity and gliosis in the rd10 retina, during the course of degeneration and neuroprotection (Figure ).…”

Section: Discussionmentioning

confidence: 99%

“…Müller cell gliosis can be characterized by the upregulation of glial fibrillary acidic protein (GFAP) (Bringmann et al, ; Fernandez‐Sanchez et al, ; Roche, Wyse‐Jackson, Byrne, et al, ). Microglia‐Müller glia crosstalk has been implicated in retinal degeneration and neuroprotection (Abcouwer, ; Arroba, Alvarez‐Lindo, van Rooijen, & de la Rosa, ; Wang, Ma, Zhao, Fariss, & Wong, ; Wang & Wong, ). In co‐culture, activated microglia induce morphological changes and inflammatory cytokine release in Müller glia (Wang et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Microglial‐induced Müller cell gliosis is attenuated by progesterone in a mouse model of retinitis pigmentosa

Roche

Ruiz-Lopez

Moloney

et al. 2017

Glia

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Norgestrel, a progesterone analogue, has demonstrated neuroprotective effects in a mouse model of retinitis pigmentosa. Neuroprotection is achieved in part through Norgestrels anti-inflammatory properties, alleviating detrimental microglial activity. Gliosis is a feature of many neurodegenerative diseases of the retina, including retinitis pigmentosa. Müller glia, a type of macroglia found in the retina, are major contributors of gliosis, characterized by the upregulation of glial fibrillary acidic protein (GFAP). Microglia-Müller glia crosstalk has been implicated in the initiation of gliosis. In the rd10 retina, increased microglial activity and gliotic events are observed prior to the onset of photoreceptor loss. We hypothesized that Norgestrels dampening effects on harmful microglial activity would consequently impact on gliosis. In the current study, we explore the role of microglia-Müller glia crosstalk in degeneration and Norgestrel-mediated neuroprotection in the rd10 retina. Norgestrels neuroprotective effects in the rd10 retina coincide with significant decreases in both microglial activity and Müller cell gliosis. Using a Müller glial cell line, rMC-1, and isolated microglia, we show that rd10 microglia stimulate GFAP production in rMC-1 cells. Norgestrel attenuates gliosis through direct actions on both microglia and Müller glia. Norgestrel reduces the release of harmful stimuli from microglia, such as interferon-γ, which might otherwise signal to Müller glia and stimulate gliosis. We propose that Norgestrel also targets Müller cell gliosis directly, by limiting the availability of pSTAT3, a known transcription factor for GFAP. These findings highlight an important aspect to Norgestrels neuroprotective effects in the diseased retina, in combating Müller cell gliosis.

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“…The pathogenesis of DR is extremely complicated. The regulating process involves multiple retinal cells such as retinal astrocytes, Muller, microglia, and pigment epithelial cells, and VEGF is expressed in all of these cells (Grigsby et al 2012;Abcouwer 2017). Vascular endothelial growth hormone (VEGF) is the most potent vasoactive factor; the normal expression of which is necessary for maintaining the structural and functional homeostasis of the retinal cells, but whose overexpression could lead to retinal angiogenesis in the presence of pathological factors such as hypoxia and hyperglycemia (Kennedy and Frank 2011;Sorrentino et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Vascular endothelial growth factor +405G/C polymorphism as a predictor of diabetic retinopathy

et al. 2020

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Background: Diabetic retinopathy is a multistage event, and the most important of it is angiogenesis. The possible association between vascular endothelial growth factor (VEGF) +405G/C gene polymorphism and various diseases, in which angiogenesis might be critical in disease development, encourages many investigators to study its role in diabetic retinopathy (DR) development in diabetics. The aim of this work is to investigate +405G/C polymorphism of VEGF gene in Egyptian patients with type 1 diabetes mellitus (T1DM) and to assess its possible role as a predictor for the development and progress of diabetic retinopathy. A cross-sectional, observational study was undertaken in a sample of type I diabetic patients who attend diabetes polyclinic of RIO Hospital, Giza, Egypt, between October 2012 and December 2016 and who were willing to participate. Two hundred and sixty-six type 1 diabetic patients were studied (108 males and 158 females). All subjects were analyzed for VEGF +405G/C polymorphism by real-time PCR using TaqMan pre-designed single nucleotide polymorphism (SNP) genotyping assay. Results: There were increased serum levels of VEGF in T1DM suffering from DR compared to those without. Also, there was increased +405 C/C of VEGF polymorphism and C allele frequency related to the severity of DR (nonproliferative retinopathy (NPR), proliferative diabetic retinopathy (PDR), and macular edema (ME)) and type C phenotype (ischemic) in T1DM suffering from DR. Conclusion: Serum levels of VEGF and its +405G/C polymorphism could be used in the evaluation, development, and progression of DR.

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Müller Cell–Microglia Cross Talk Drives Neuroinflammation in Diabetic Retinopathy

Cited by 53 publications

References 18 publications

The NLRP3 Inflammasome May Contribute to Pathologic Neovascularization in the Advanced Stages of Diabetic Retinopathy

The NLRP3 Inflammasome May Contribute to Pathologic Neovascularization in the Advanced Stages of Diabetic Retinopathy

Microglial‐induced Müller cell gliosis is attenuated by progesterone in a mouse model of retinitis pigmentosa

Vascular endothelial growth factor +405G/C polymorphism as a predictor of diabetic retinopathy

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