Neuroinflammation in glaucoma: A new opportunity

Abstract

Mounting evidence suggests neuroinflammation is a key process in glaucoma, yet the precise roles are not known. Understanding these complex processes, which may also be a key in other common neurodegenerations such as Alzheimer's disease, will lead to targeted therapeutics for a disease that affects as many as 80 million people worldwide. Here, we define neuroinflammation as any immune-relevant response by a variety of cell types including astrocytes, microglia, and peripherally derived cells occurring in the optic nerve head and/or retina. In this review article, we first discuss clinical evidence for neuroinflammation in glaucoma and define neuroinflammation in glaucoma. We then review the inflammatory pathways that have been associated with glaucoma. Finally, we set out key research directions that we believe will greatly advance our understanding of the role of neuroinflammation in glaucoma. This review arose from a discussion of neuroinflammation in glaucoma at the 2015 meeting of The Lasker/IRRF Initiative for Innovation in Vision Science. This manuscript sets out to summarize one of these sessions; "Inflammation and Glaucomatous Neurodegeneration", as well as to review the current state of the literature surrounding neuroinflammation in glaucoma.

Keywords: Astrocyte; Glaucoma; Inflammation; Lasker; Microglia; Monocyte; Neurodegeneration.

Figure 1. Neuroinflammation in glaucoma

Many aspects of neuroinflammation in glaucoma are similar to what has been shown in other diseases. Although much is still to be determined, initiation of immune responses may occur after the release of DAMPs from RGCs (green), astrocytes (blue with processes) and/or microglia (red with processes). The TLRs expressed in glial cells activate the production and secretion of cytokines such as those of the IL-1 family. A secondary expression of cytokines, such as TNF-a in microglia and IL-6 in astrocytes, is induced, leading to an amplified inflammatory response, that may include infiltration of peripherally derived immune cells (blue, no processes). These neuroinflammatory responses are likely modulated by complement proteins, such as C1qa, in the ONH. In addition, intrinsic up-regulation of complement molecules in RGCs (such as C1qa and C3) occurs early and mediates synaptic dysfunction. From Soto and Howell 2015 (Soto and Howell, 2014).

Figure 2. The major glial types in the optic nerve head in glaucoma

(A) GFP positive astrocytes in the glial lamina of mice with no glaucomatous neurodegeneration. From Lye-Barthel and Jakobs 2013 (Lye-Barthel et al., 2013), (B) Microglia responding to early neuron degeneration in the retina of a rat model of glaucoma. Adapted from Naskar et al, 2002 (Naskar et al., 2002), (C) Infiltrating, peripherally derived immune cells enter the optic nerve head during early stages of DBA/2J glaucoma. Adapted from Howell et al, 2012 (Howell et al., 2012).

Figure 3. The human microbiome may affect glaucomatous neurodegeneration

(A) Differences in oral bacterial load in a cohort of African-American patients with and without glaucoma. Normalized oral bacterial load (NOBL) of patients with glaucoma were higher than those of subjects without glaucoma (p<0.017, t-test). Although cases were significantly different from controls in age (p<0.008, t-test), gender (p<0.02 Chi-square) and diabetes status (p<0.021, Chi square), GLM ANOVA of NOBLs (using group, gender, diabetes status and age [above or below median value] as independent variables) revealed a significant effect of group status (whether a subject belonged to cases or controls) only (p<0.024) while all other parameters did not show a statistically significant effect (p>0.26 for all). B. Microbial components affect neurodegeneration in glaucoma animal models. Peripheral lipopolysaccharide (LPS) administration significantly accelerates glaucomatous pathology in DBA/2J mice (but not in the non-glaucomatous DBA/2J-Pe mice) as well as in the microbead-induced IOP elevation model of glaucoma in C57BL/6 mice (not shown here). LPS (60 μg) was injected into one hind footpad of 6-month old male DBA/2J and DBA/2J-Pe mice and retinal damage was assessed at 8 months of age. Computer-assisted counts of total RGCs per retina (n = 18 and n = 24 retinas for DBA/2J and DBA/2J+LPS, respectively; n = 4 and n = 10 retinas for DBA/2J-Pe and DBA/2J-Pe+LPS, respectively) show increased RGC loss in DBA/2J mice treated with LPS. Data are presented as mean ± SEM. Statistical differences were assessed by one-way ANOVA, followed by Tukey-Kramer post-hoc testing (**p<0.01). Adapted from Astafurov et al, 2014 (Astafurov et al., 2014).