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Isabella Palazzo, Levi Todd, Xiaoyu Liu, Ning Quan, Andrew J Fischer; IL-1β conveys neuroprotection via astrocytic IL1R1 signaling following excitotoxic retinal injury. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4013.
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© ARVO (1962-2015); The Authors (2016-present)
Microglia and inflammatory signaling have context-dependent impacts on neuronal survival after injury, and have been shown to influence astrocyte reactivity to mediate this effect. The role microglia play in regulating neuronal cell death after excitotoxic injury in the retina is not fully understood. This study investigates the role of microglia and the inflammatory cytokine IL1β in NMDA-induced cell death in the mouse retina.
Mice aged P40-P60 were used for all experiments. Mice lines used include IL1R1-tdTomato reporter, IL1R1 null (IL1R1r/r), and GFAPcre-IL1R1r/r. GFAPCre-IL1R1r/r mice were derived from GFAP>Cre x homozygous knock-in stop-fl/fl-IL1R1-IRES-tdTomato mice that were crossed onto the IL1R1-null background to restore IL1R1 expression only in astrocytes. Retinas were treated with IL1β via intravitreal injections of recombinant mouse IL1β (200ng/dose). Excitotoxic retinal damage was induced via intraocular injections of NMDA (38.5 μg/dose). Eyes were enucleated and retinas were processes for IHC and TUNEL assays. Cell counts were performed, and significance of difference was determined using one-way ANOVA followed by Tukey’s test for multiple comparisons.
IL1β treatment prior to NMDA damage decreases the number of TUNEL+cells 24 hours after damage (ctrl 38.8±5, trt 14.3±3; n≥6; p<.01). In an IL1R1-reporter mouse line, we find expression in bipolar cells, astrocytes, endothelial cells and few Müller glia. Patterns of expression did not differ between control, NMDA-treated, and IL1β-treated retinas. Treatment with IL1β prior to NMDA damage in IL1R1 null mice results in no significant difference in the number of TUNEL+cells (ctrl 22.3±12, trt 31.2±18; n=8; p=0.3). Treatment with IL1β prior to NMDA in GFAPcre-IL-1R1r/r mice, which have IL-1R1 expression restricted to only astrocytes, results in a significant decrease in the number of TUNEL+cells in both the inner nuclear layer (ctrl 17.3±9.4, trt 8.6±5.6n=8; p=.04), and ganglion cell layer (ctrl 21.3±5.6, trt 8±3.5 ; n=8 ;p<.01).
We conclude that a single high dose of IL1β can promote neuronal survival following excitotoxic injury, and IL1R1 expression is required for this effect. IL1R1 expression in astrocytes alone is sufficient for IL1β-mediated neuroprotection. Our data support the hypothesis that IL1β signaling through IL1R1 on astrocytes mediates the survival of damaged ganglion cells.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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