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Gina Nicole Wilson, Matthew Alan Smith, Christine Dengler-Crish, Denise M Inman, Samuel D Crish; Characterization of cytokine levels in the DBA/2J mouse model of glaucoma. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2453.
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© ARVO (1962-2015); The Authors (2016-present)
Microglial activation and cytokine signaling are prominent features of neurodegenerative disorders and may be associated with axonal transport deficits seen in the retinal ganglion cell (RGC) projection in the DBA/2J glaucomatous mouse model. Little is known about cytokine activity outside of the retina - regions where very early changes are seen in glaucoma.
DBA/2J and DBA/2J.Gpnmb+ (control) mice were intravitreally injected with anterograde tracer cholera toxin subunit B (CTB) and sacrificed 48-hrs later. Histological sections of the visual projection were taken and assayed for markers of microglial number and activation; in other samples, visual structures were microdissected from fresh tissue based on transport outcome. Using magnetic bead multiplexing assays, we measured 20 different cytokines in retina, proximal and distal optic nerves (pON/dON), CTB-positive and -negative SC subdivisions, cerebellum, and serum at different ages (n=34 projections; 6-8 per group).
Retinal FGF-2 was elevated in DBA/2J mice at all ages by 25% or more; also, significant elevations in retinal IL-12, IFN-γ, MIG, MIP-1α, IL-5 and KC were observed in young DBA/2Js compared to controls, followed by a concomitant, age-dependent decrease in the DBA/2Js. Proximal ON of young DBA/2Js showed a 50% or greater decrease in levels of VEGF, IL-6, IL-17, IL-2, MIP-1α, TNF-α, IL-4; FGF-2, MIG, and KC compared to older DBA/2J cohorts and controls. These cytokines were also attenuated in pON of young DBA/2Js to a lesser degree. Age-dependent elevations in VEGF, FGF-2, IL-6, IL-17, IL-2, MIG, MIP-1α, TNF-α, IL-4, and KC were shown in the dON for controls but not in DBA/2J mice. Collicular cytokine levels were elevated in young DBA/2J and were followed by age-dependent decreases in FGF-2 and IL-12. Pro-inflammatory cytokine IL-6 varied in accordance with transport outcome in the SC: IL-6 was elevated 44-80% in old DBA/2J SC regions lacking anterograde transport from RGCs compared to areas with intact transport. We observed increased microglial number and activation with increasing age and axonal pathology in ON and SC of our DBA/2Js.
Dysregulation of cytokine signaling in the retinal projection of DBA/2J mice is evident early in pathology in the distal retinal targets. Cytokines may signal the progression of pathological changes in the visual projection of DBA/2J mice prior to functional transport loss and RGC death.
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