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Kazuya Oikawa, Julie A Kiland, N.Matthew Ellinwood, Gillian J McLellan; Neuro-inflammation and degeneration in the Optic Nerve Head (ONH) in a Genetic Feline Model of Glaucoma. Invest. Ophthalmol. Vis. Sci. 2019;60(9):673.
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© ARVO (1962-2015); The Authors (2016-present)
To characterize microglial activation status and determine the relationship between ONH microglial activation, IOP and axon loss in feline congenital glaucoma (FCG), a spontaneous model with ONH structure similar to humans.
Relative activation of microglia and macrophages was investigated in the ONH of 21 LTBP2-/- cats with FCG and 15 age-matched wt controls, ranging in age from neonates to adults. IOP data were collected at least weekly throughout life and optic nerve axon counts were obtained using previously validated methods. ONH cell types were identified by immunofluorescent (IF) labeling with GFAP, IBA1 and OLIG2. Confocal microscopy images were analyzed for each ONH sub-region (pre-laminar [PL]; lamina cribrosa [LC], retro-laminar [RL]). Expression of microglial and inflammatory genes were quantified by qPCR and localized by RNAscope in situ hybridization (ISH) combined with IF on adult feline ONH tissue. Data were compared between groups by two-tailed unpaired t-test or Mann-Whitney test and associations between variables were evaluated by linear regression models with p<0.05 considered significant.
No significant difference in ONH IBA1+ cell density was detected between FCG neonates (prior to IOP elevation) and wt controls (p = 0.89). IBA1+ cell density in PL and RL regions showed significant positive association with mean and maximum IOP (p < 0.01) at both early (2-4 weeks of IOP elevation, no axon damage) and chronic (adult cats, IOP elevation, varying degrees of axon damage) stages of disease. IBA1+ cell density throughout the ONH was negatively correlated with axon count (p < 0.0001) in chronic disease. qPCR identified enhanced expression of neurodegeneration-associated microglial markers and pro-inflammatory genes (localized to IBA1+ cells by ISH and IF) and down-regulation of homeostatic microglial markers in adult chronic FCG (Fig.1). A subset of IBA1+ ONH microglia (confirmed by co-labeling with a microglia specific marker) in chronic FCG expressed lipoprotein lipase (LPL), implicating a possible role for processing of axonal/myelin debris (Fig.2).
ONH microglial activation is dynamic and regionally heterogeneous and is associated with magnitude of IOP and axon loss in this glaucoma model. Our data emphasize the temporal and spatial complexity of roles played by distinct ONH glial populations in glaucoma pathogenesis.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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