Microglia mediate non‐cell‐autonomous cell death of retinal ganglion cells. Issue 11 (29th October 2018)

• Record Type: Journal Article
• Authors: Takeda, Akiko; Shinozaki, Youichi; Kashiwagi, Kenji; Ohno, Nobuhiko; Eto, Kei; Wake, Hiroaki; Nabekura, Junichi; Koizumi, Schuichi
• Is Part Of: Glia. Volume 66:Issue 11(2018)
• Page Start: 2366
• Page End: 2384
• Publication Date: 2018-10-29
• Subjects: cytokines -- excitotoxicity -- microglia -- retinal ganglion cells -- tumor necrosis factor; Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.23475
• Languages: English
• ISSNs: 0894-1491

Abstract

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:: DTA tetO/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. Main Points: Microglia have a critical role for the N ‐methyl‐d ‐aspartate (NMDA)‐induced neuronal damages in the retina, although they do not respond to NMDA directly. For such microglia‐mediated noncell‐autonomous mechanisms, TNFα has a central role.