Abstract
Signaling mediated by cytokines and chemokines is involved in glaucoma-associated neuroinflammation and in the damage of retinal ganglion cells (RGCs). Using multiplexed immunoassay and immunohistochemical techniques in a glaucoma mouse model at different time points after ocular hypertension (OHT), we analyzed (i) the expression of pro-inflammatory cytokines, anti-inflammatory cytokines, BDNF, VEGF, and fractalkine; and (ii) the number of Brn3a+ RGCs. In OHT eyes, there was an upregulation of (i) IFN-γ at days 3, 5, and 15; (ii) IL-4 at days 1, 3, 5, and 7 and IL-10 at days 3 and 5 (coinciding with downregulation of IL1-β at days 1, 5, and 7); (iii) IL-6 at days 1, 3, and 5; (iv) fractalkine and VEGF at day 1; and (v) BDNF at days 1, 3, 7, and 15. In contralateral eyes, there were (i) an upregulation of IL-1β at days 1 and 3 and a downregulation at day 7, coinciding with the downregulation of IL4 at days 3 and 5 and the upregulation at day 7; (ii) an upregulation of IL-6 at days 1, 5, and 7 and a downregulation at 15 days; (iii) an upregulation of IL-10 at days 3 and 7; and (iv) an upregulation of IL-17 at day 15. In OHT eyes, there was a reduction in the Brn3a+ RGCs number at days 3, 5, 7, and 15. OHT changes cytokine levels in both OHT and contralateral eyes at different time points after OHT induction, confirming the immune system involvement in glaucomatous neurodegeneration.
Highlights
Glaucoma is a multifactorial neurodegenerative disease, characterized by progressive damage of the optic nerve produced by retinal ganglion cells’ (RGCs) death [1]
In the same unilateral laser-induced ocular hypertension (OHT) experimental model, and at the same time points after OHT induction, the aim of the current study was to analyze both in OHT and contralateral eyes: (i) the expression of different mediators of inflammation both with neuroprotective and anti-inflammatory properties (IL-4, Interleukin 10 (IL-10), Brain-Derived Neurotrophic Factor (BDNF), Vascular Endothelial Growth Factor (VEGF)) and with pro-inflammatory properties (TNF-α, IL-1β, Interleukin 6 (IL-6), interleukin 17 (IL-17), IFN-γ), as well as a microglial activation regulator such as fractalkine (CX3CL1), using multiplex assay and immunohistochemical techniques, and (ii) the relationship between the expression of these factors and the decrease in the number of RGCs that occurs after OHT induction
We found a significant increase in IL-6 in OHT eyes at days 1, 3, and 5 after OHT induction with respect to naïve eyes, being expressed by microglial cells, as we observed in our immunohistochemical study
Summary
Glaucoma is a multifactorial neurodegenerative disease, characterized by progressive damage of the optic nerve produced by retinal ganglion cells’ (RGCs) death [1]. Activated microglia can alter the expression of different receptors such as cell surface transmembrane glycoprotein CD200 receptor (CD200R), receptor for the CX3C chemokine fractalkine (CX3CR1), and purinergic receptor P2Y12 (P2RY12) and can modify their gene expression, promoting the synthesis and release of inflammatory cytokines (tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), etc.) [10,11,12]. These cytokines may be involved in the apoptosis of RGCs activated by both intrinsic and extrinsic pathways, exacerbating the neurodegenerative process [13,14]. In the experimental models of glaucoma and in the aqueous humor, serum, and retina of glaucoma patients, an increase in inflammatory mediators (IL-1β, interleukin 4 (IL-4), IL-6, interleukin 10 (IL-10), interleukin 12 (IL -12), interferon gamma (IFN-γ), vascular endothelial growth factor (VEGF), and TNF-α) has been found [15,16,17,18]
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