The Role of Neuroinflammation in Glaucoma: An Update on Molecular Mechanisms and New Therapeutic Options

Abstract

Glaucoma is a multifactorial optic neuropathy characterized by the continuous loss of retinal ganglion cells, leading to progressive and irreversible visual impairment. In this minireview, we report the results of the most recent experimental studies concerning cells, molecular mechanisms, genes, and microbiome involved in neuroinflammation processes correlated to glaucoma neurodegeneration. The identification of cellular mechanisms and molecular pathways related to retinal ganglion cell death is the first step toward the discovery of new therapeutic strategies. Recent experimental studies identified the following possible targets: adenosine A2A receptor, sterile alpha and TIR motif containing 1 (neurofilament light chain), toll-like receptors (TLRs) 2 and 4, phosphodiesterase type 4 (PDE4), and FasL-Fas signaling (in particular ONL1204, a small peptide antagonist of Fas receptors), and therapies directed against them. The continuous progress in knowledge provides interesting data, although the total lack of human studies remains an important limitation. Further research is required to better define the role of neuroinflammation in the neurodegeneration processes that occur in glaucomatous disease and to discover neuroprotective treatments amenable to clinical trials. The hereinafter reviewed studies are reported and evaluated according to their translational relevance.

Ocular Neurodegenerative Diseases: Interconnection between Retina and Cortical Areas

“…The reduction in energy production and the increase in the production of free radicals at the mitochondrial level are to be considered as potential additional mechanisms in the etiopathogenesis of glaucoma. Definitely, the identification of cellular mechanisms and molecular pathways related to retinal ganglion cell death is the first step toward the discovery of new therapeutic strategies to control glaucoma [ 87 , 88 ].…”

Risk Factors for Retinal Ganglion Cell Distress in Glaucoma and Neuroprotective Potential Intervention

“…The edema formation, in turn, disrupts the functioning of surrounding cells by compression [ 119 ]. Moreover, the increase in the Major Histocompatibility Complex Class I and II by VEGF and the Heat Shock Proteins leads to the activation of an adaptive immune response and, consequently, the disruption of the BRB [ 111 , 120 ].…”

The Future of Stem Cells and Their Derivates in the Treatment of Glaucoma. A Critical Point of View

“…The connection between neuroinflammation and glaucoma has been proved in animal models, but there are also clinical data supporting it. The analogies with neurodegenerative diseases that were recently revealed to be correlated with inflammatory responses (amyotrophic lateral sclerosis, Alzheimer's, Parkinson's, Huntington's disease, and frontotemporal dementia) suggest that similar cellular players, molecular mechanisms, genes and the microbiome are involved in glaucoma-related neurodegeneration [28][29][30]. Common features of these neurodegenerative diseases are strongly age-related incidence, and similar mechanisms of cell injury (oxidative stress, mitochondrial dysfunction, alterations in the ubiquitin-proteasome system, glutamate excitotoxicity, glial activation and inflammation, deposition of protein aggregates in specific anatomical areas) with the result of neuronal death [31].…”

“…These cells offer metabolic support to neurons, neuroprotection and regulate the synaptic activity. Microglial cells are CNS-resident innate immune cells, migratory blood monocytes to the CNS that retain monocyte-specific antigens CD11b/c, complement peptide C3a receptor 1 (C3aR1) and chemokine receptor (CX3CR1) [28,34]. The activation of microglia is an early event in the retina and optic nerve during glaucoma.…”

“…Depending on this interaction via signaling proteins (such as complement factors, TNF-α) and their receptors (Interleukin-1β (IL-1β), IL-6) [27], astroglia are differentiated into A1 astrocytes with neurotoxic effects or A2 astrocytes with neuroprotective properties. The neuroinflammatory process also induces the differentiation of microglia into M1 (proinflammatory) or M2 (anti-inflammatory) activated macrophages [28]. The interplay between A1/A2 astrocytes and M1/M2 microglia will determine the extent of neuronal damages, i.e., RGCs death.…”