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Markus Spurlock, Weijun An, Tsung-Han Chou, Galina Reshetnikova, Hua Wang, Vittorio Porciatti, Valery Shestopalov; Neuroinflammation after transient intraocular pressure fluctuations drives retinal ganglion cell disfunction and death. Invest. Ophthalmol. Vis. Sci. 2022;63(7):917 – A0386.
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© ARVO (1962-2015); The Authors (2016-present)
Transient intraocular pressure spikes (spOHT) are induced by certain activities, including yoga, playing wind instruments, and caffeine intake, and are associated with an increased risk of glaucoma. To understand mechanisms underlying the spOHT-induced retinal ganglion cell (RGC) loss, we examine the role of innate immune response in RGC disfunction in a rodent model of non-ischemic IOP spikes.
C57BL/6J mice (2-3 month) were challenged by either “spiking” IOP changes (spOHT) or by a steady elevation (stOHT) at 40mm Hg above baseline via cannulation of the anterior eye chamber. For spOHT, the reservoir is elevated 1 minute and then lowered for 1 minute for seven cycles. For steady stress, the column remains raised for 7 minutes. We measured changes in intravitreal IL1-β using ELISA, and monitored activation of GsdmD, NLRP1, caspases-1 in retina by qRT-PCR. Retinal function was measured with pattern electroretinogram (PERG). RGC counts were performed on whole mount retina with RBPMS antibody at 7 days after stress. The role of inflammasome was examined using Caspase 1, NLRP1, and GSDMD null mice. TRPV1 blocker was administered to test the role of mechanical stress signaling. Data were evaluated with ANOVA with multiple comparisons to controls.
Fluorescent label showed caspase 1, caspase 3, and GSDMD activation in RGCs 6 hours after spOHT. IL1β measured in vitreous at 6, 12, and 24 hours post spOHT showed 1, 12, and 13 fold increase. qRT-PCR showed significant transcription increase in retina for casp1, NLRP1, and GSDMD at 24h after spOHT. PERG revealed a decline in amplitude of 31.8% at 1 week following spOHT. RBPMS+ cell counts of retina at 1 week also showed 22.6% reduction in cells per sampled regions. Significant inflammasome markers and functional and structural loss were not observed in the stOHT group. Casp1 knull mice demonstrated reduced loss in PERGamp (1.8%) and RBPMS+ (7.7%) count at 1 week, as did NLRP1 null (10%), (5.9%), and GSDMD null (18%), (4.7%) after spOHT. TRPV4 blocker treatment prior to spOHT ablated singificant deficts in PERGamp (5%) and RBPMS+ (3.1%).
Rapid IOP fluctuations drive innate immune responses in retinal ganglion cells, leading to functional disruption and cell loss. Ablation of inflammation-initiating proteins, as well as blockade of pressure-sensitive TRPV4 channel protected from functional disruption.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
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