Microglia mediate non‐cell‐autonomous cell death of retinal ganglion cells

Abstract

Excitotoxicity is well known in the neuronal death in the brain and is also linked to neuronal damages in the retina. Recent accumulating evidence show that microglia greatly affect excitotoxicity in the brain, but their roles in retina have received only limited attention. Here, we report that retinal excitotoxicity is mediated by microglia. To this end, we employed three discrete methods, that is, pharmacological inhibition of microglia by minocycline, pharmacological ablation by an antagonist for colony stimulating factor 1 receptor (PLX5622), and genetic ablation of microglia using Iba1‐tTA::DTAtetO/tetO mice. Intravitreal injection of NMDA increased the number of apoptotic retinal ganglion cells (RGCs) followed by reduction in the number of RGCs. Although microglia did not respond to NMDA directly, they became reactive earlier than RGC damages. Inhibition or ablation of microglia protected RGCs against NMDA. We found up‐regulation of proinflammatory cytokine genes including Il1b, Il6 and Tnfa, among which Tnfa was selectively blocked by minocycline. PLX5622 also suppressed Tnfa expression. Tumor necrosis factor α (TNFα) signals were restricted in microglia at very early followed by spreading into other cell types. TNFα up‐regulation in microglia and other cells were significantly attenuated by minocycline and PLX5622, suggesting a central role of microglia for TNFα induction. Both inhibition of TNFα and knockdown of TNF receptor type 1 by siRNA protected RGCs against NMDA. Taken together, our data demonstrate that a phenotypic change of microglia into a neurotoxic one is a critical event for the NMDA‐induced degeneration of RGCs, suggesting an importance of non‐cell‐autonomous mechanism in the retinal neuronal excitotoxicity.

Nogo-A-targeting antibody promotes visual recovery and inhibits neuroinflammation after retinal injury

“…For microglia/macrophages, the most striking change was the downregulation of TNFα expression in injured retinae. The enhancement of TNFα expression in microglia is a major event controlling retinal excitotoxicity 67 . The elimination or the inhibition of microglia has been shown to prevent NMDA-induced TNFα upregulation in the retina and to protect RGCs from cell death 67 .…”

“…The enhancement of TNFα expression in microglia is a major event controlling retinal excitotoxicity 67 . The elimination or the inhibition of microglia has been shown to prevent NMDA-induced TNFα upregulation in the retina and to protect RGCs from cell death 67 . Given the strong decrease in TNFα expression observed after 11C7 injection, Nogo-A-Delta 20 appears as a new potent modulator of TNFα expression in microglia.…”

Methodological Improvements With Conductive Materials for Volume Imaging of Neural Circuits by Electron Microscopy

“…In addition, embedding Ketjen black into resin ameliorates image deformation caused by insufficient sample conductivity, improves slicing quality and facilitates acquisition of serial images at higher resolution (Nguyen et al, 2016 ). Conductive resins based on carbon black fillers substantially reduce charging artifacts, result in better ultrastructural data and are applicable to various types of tissues in SBEM imaging (Nguyen et al, 2016 , 2018 ; Thai et al, 2016 , in press ; Yoshimura et al, 2017 ; Saitoh et al, 2018 ; Sawada et al, 2018 ; Takeda et al, 2018 ).…”

Neuroprotective Strategies for Retinal Ganglion Cell Degeneration: Current Status and Challenges Ahead

“…Indeed, several reports show that abnormally responsive microglia can directly reduce the survival of RGCs. For example, even though microglial cells are not endowed with NMDA receptors, upon intravitreal NMDA injection, these cells detect the alterations in calcium and adenosine triphosphate (ATP) signaling in other retinal cells, including RGCs, by increasing the inflammatory response [222]. Interestingly, the report that isolated RGCs are resistant to NMDA excitotoxicity [223], while in the retina NMDA exposure leads to RGCs degeneration triggered by increased production of tumor necrosis factor (TNF) and abnormal behavior of microglial cells [222] is another evidence of the role of microglial cells shaping RGCs degeneration.…”