Abstract
BackgroundMicroglia and inflammation have context-specific impacts upon neuronal survival in different models of central nervous system (CNS) disease. Herein, we investigate how inflammatory mediators, including microglia, interleukin 1 beta (IL1β), and signaling through interleukin 1 receptor type 1 (IL-1R1), influence the survival of retinal neurons in response to excitotoxic damage.MethodsExcitotoxic retinal damage was induced via intraocular injections of NMDA. Microglial phenotype and neuronal survival were assessed by immunohistochemistry. Single-cell RNA sequencing was performed to obtain transcriptomic profiles. Microglia were ablated by using clodronate liposome or PLX5622. Retinas were treated with IL1β prior to NMDA damage and cell death was assessed in wild type, IL-1R1 null mice, and mice expressing IL-1R1 only in astrocytes.ResultsNMDA-induced damage included neuronal cell death, microglial reactivity, upregulation of pro-inflammatory cytokines, and genes associated with IL1β-signaling in different types of retinal neurons and glia. Expression of the IL1β receptor, IL-1R1, was evident in astrocytes, endothelial cells, some Müller glia, and OFF bipolar cells. Ablation of microglia with clodronate liposomes or Csf1r antagonist (PLX5622) resulted in elevated cell death and diminished neuronal survival in excitotoxin-damaged retinas. Exogenous IL1β stimulated the proliferation and reactivity of microglia in the absence of damage, reduced numbers of dying cells in damaged retinas, and increased neuronal survival following an insult. IL1β failed to provide neuroprotection in the IL-1R1-null retina, but IL1β-mediated neuroprotection was rescued when expression of IL-1R1 was restored in astrocytes.ConclusionsWe conclude that reactive microglia provide protection to retinal neurons, since the absence of microglia is detrimental to survival. We propose that, at least in part, the survival-influencing effects of microglia may be mediated by IL1β, IL-1R1, and interactions of microglia and other macroglia.
Highlights
Microglia and inflammation have context-specific impacts upon neuronal survival in different models of central nervous system (CNS) disease
translocator protein (TSPO) has been reported as a marker for reactive microglia and has been implicated with the ligand Dbi as coordinating pro-inflammatory signals between microglia and Müller glia in the retina [32, 33]
We found that TSPO is upregulated in both microglia and Müller glia, whereas Dbi is upregulated in microglia and downregulated in Müller glia in NMDA-damaged retinas (Additional file 1: Figure S1), consistent with a recent report [34]
Summary
Microglia and inflammation have context-specific impacts upon neuronal survival in different models of central nervous system (CNS) disease. In a mouse model of glaucoma, upregulation of complement occurs prior to the onset of ganglion cell death, which tags synapses of ganglion cells to be targeted for engulfment by microglia [13]. In support of this finding, inhibition of complement suppresses the degeneration of RGCs in glaucomatous mouse retinas [14]. In a mouse model of hemorrhagic macular degeneration, treatment with minocycline prevents microglia accumulation in the sub-retinal space and increased photoreceptor survival [15]. Considered together, microglia can be beneficial or harmful to neuronal survival and the survival-influencing actions of microglia are context-specific
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