Abstract
BackgroundNeuroinflammation—astrogliosis, microglial activation, and changes in cytokine signaling—is a prominent feature of neurodegenerative disorders. Glaucoma is a group of chronic neurodegenerative conditions that make up the leading cause of irreversible blindness worldwide. Neuroinflammation has been postulated to play a significant role in the pathogenesis and progression of glaucomatous neurodegeneration. Though much is known regarding inflammation in the eye in glaucoma, little is known about cytokine activity outside of the retina where pathologies develop early.MethodsWe traced the primary visual projection from the eye to the superior colliculus (SC) in DBA/2J and DBA/2J.Gpnmb+ (control) mice using the anterograde tracer cholera toxin-B (CTB) to assay axonal transport deficits. Forty-eight hours later, visual structures were microdissected from fresh tissue based on transport outcome. Using magnetic bead multiplexing assays, we measured levels of 20 cytokines in the retina, proximal and distal optic nerves, CTB-positive and negative SC subdivisions, cerebellum, and serum at different ages representing different stages of pathology.ResultsPro- and anti-inflammatory cytokine levels in mice often changed in the same direction based on strain, age, and tissue. Significant elevations in retinal pro-inflammatory cytokines were observed in young DBA/2J mice compared to controls, followed by an age-dependent decrease in the DBA/2J mice. Proximal optic nerve of young DBA/2J mice showed a 50 % or greater decrease in levels of certain cytokines compared to older DBA/2J cohorts and controls, while both proximal and distal optic nerve of DBA/2Js showed elevations in IL-1β at all ages compared to controls. Pro-inflammatory cytokine IL-6 levels varied in accordance with transport outcome in the SC: IL-6 was elevated 44–80 % in glaucomatous DBA/2J collicular regions deficient in anterograde transport from retinal ganglion cells (RGCs) compared to areas with intact transport.ConclusionDysregulation of cytokine signaling in the RGC projection of DBA/2J mice was evident early in distal retinal targets, well before intraocular pressure elevation or axonal degeneration begins.
Highlights
Neuroinflammation—astrogliosis, microglial activation, and changes in cytokine signaling—is a prominent feature of neurodegenerative disorders
The following pro-inflammatory cytokines peaked at 8–10 months of age in DBA/2J retinas, reaching levels that were significantly greater than DBA/2J-Gpnmb+ mice (D2G) controls: vascular endothelial growth factor (VEGF) (F3, 39 = 3.098, p = 0.032), IL-17 (F3, 39 = 3.693, p = 0.034), IL-1α (F3, 36 = 2.924, p = 0.029), tumor necrosis factor-α (TNF-α) (F3, 38 = 3.051, p = 0.029), and IFN-γ (F3, 37 = 3.904, p = 0.033)
No significant differences between old and young D2G retina were shown for the following cytokines: fibroblast growth factor (FGF)-2 (t(9) = −2.173, p = 0.058), IL-10 (t(6) = 0.389, p = 0.711), IL-5 (t(10) = −0.166, p = 0.871), VEGF (t(10) = 0.339, p = 0.742), IL-12 (t(10) = 1.000, p = 0.341), IL-17 (t(10) = 1.213, p = 0.92), IL-1α (t(10) = 0.552, p = 0.593), TNF-α (t(10) = −0.411, p = 0.690), IFN-γ (t(9) = −0.333, p = 0.747), MIG (t(10) = −0.385, p = 0.708), macrophage inflammatory protein-1α (MIP-1α) (t(10) = 1.206, p = 0.255), and keratinocyte chemoattractant (KC) (t(10) = −0.957, p = 0.361)
Summary
Neuroinflammation—astrogliosis, microglial activation, and changes in cytokine signaling—is a prominent feature of neurodegenerative disorders. Though much is known regarding inflammation in the eye in glaucoma, little is known about cytokine activity outside of the retina where pathologies develop early. Given the common incidence of elevated IOP without glaucomatous vision loss as well as normal tension glaucoma, it is clear that many other factors play a role in the development and progression of this degenerative disease [14,15,16]. Abnormal activation of the immune system has been shown to produce glaucomatous pathology in the absence of elevated IOP [14]. Bosco and colleagues have shown microglial activation within young DBA/2J mouse retina, pre-laminar optic nerve, and nerve head [17, 18], which suggests a role for immunomodulatory molecules such as cytokines early in pathology in moderately elevated IOP contexts. Models of high IOP and nerve crush have demonstrated some reliance on immunomodulation for either protection [19] or propagation of damage [20]
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