The complex role of neuroinflammation in glaucoma

Abstract

Glaucoma is a multifactorial neurodegenerative disorder affecting 80 million people worldwide. Loss of retinal ganglion cells and degeneration of their axons in the optic nerve are the major pathological hallmarks. Neuroinflammatory processes, inflammatory processes in the central nervous system, have been identified in human glaucoma and in experimental models of the disease. Furthermore, neuroinflammatory responses occur at early stages of experimental glaucoma, and inhibition of certain proinflammatory pathways appears neuroprotective. Here, we summarize the current understanding of neuroinflammation in the central nervous system, with emphasis on events at the optic nerve head during early stages of glaucoma.

Figure 1.

Inflammatory responses in the CNS are mediated by resident astrocytes and microglia. The neurovascular unit comprises neurons (green), astrocytes (blue, with processes) and components of the blood–brain barrier such as endothelial cells (red, vessel). In addition, microglia (red, with processes) sense environmental changes. Glial cells (astrocytes and microglia) express pattern recognition receptors (PRRs) such as toll-like receptors (TLRs), purinergic receptors (PRs) and scavenger receptors (SRs) to respond to DAMPs released by cells during injury or disease. The activation of these receptors promotes proinflammatory signaling that leads to the production of cytokines and chemokines. These cytokines and chemokines induce changes in the endothelial cells and blood–brain barrier integrity, resulting in recruitment of blood-derived immune cells (blue) and amplification of the innate immune response.

Figure 2.

Transendothelial migration in the CNS. Schematic representation of the different steps involved in leukocyte extravasation. Selectin ligands and molecular adhesion molecules that are up-regulated in endothelial cells at the ONH interact with selectins and integrins present at the cell surface of leukocytes, leading to leukocyte infiltration.

Figure 3.

Inhibition of TNF-α activity reduces microglial activation and axonal degeneration in the optic nerve after ocular hypertension. (A) Ocular hypertension (OHT) increased the number of Iba-1-positive microglial cells in the ONH and induced TNF-α expression in these cells. Treatment with the TNF-α inhibitor Etanercept (Etan.) significantly reduced the number of microglia and the expression of TNF-α. (B) Axonal degeneration in the optic nerve is reduced by Etanercept treatment in ocular hypertension (Roh et al. 2012). Mann-Whitney U test, ** P < 0.01 comparing control vs. Etanercept treated ocular hypertension; †† P < 0.01 comparing vehicle vs. Etanercept treated OHT. (Adapted from data in Roh et al. 2012.)

Figure 4.

Monocyte infiltration occurs early in DBA/2J glaucoma. (A) Flow cytometry revealed that the major blood-derived immune cell detected in the ONH of DBA/2J glaucomatous mice was the CD11b⁺Cd11c⁺ monocyte. These cells were completely absent in radiation-treated DBA/2J eyes (Rad-D2) or control (D2-Gp) eyes. (B) Cell infiltration was also assessed using the injection of a fluorescent tracer into the spleen (CFDA, green). Spleen-derived CFDA⁺ cells entered the optic nerves of untreated DBA/2J eyes but not Rad-D2 eyes or control eyes (Howell et al. 2012). (From Howell et al. 2013; adapted, with permission, from the authors.)

Figure 5.

The complement system is activated in human and animal models of glaucoma. (A) C1Q protein is increased in RGCs and in the inner plexiform layer of human (Tezel et al. 2010), primate (Stasi et al. 2006), and mouse (Howell et al. 2011a) retinas in response to high IOP. (B) MAC deposition is found in RGCs from C5-sufficient glaucomatous DBA/2J.C5^B6 mice (Howell et al. 2013). TUBB3, tubulin β-3; NOE, normal or early.

Figure 6.

A model of early neuroinflammatory responses in glaucoma. We hypothesize that initiation of these immune responses occurs after the release of DAMPs from RGCs, glial cells or both. 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-α in microglia and IL-6 in astrocytes, is induced, leading to an amplified inflammatory response. 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. The cell types shown here are described in the legend for Figure 1.