Immunomodulation as a Neuroprotective Strategy for Glaucoma Treatment

Abstract

Purpose of Review This review aims to highlight the current knowledge about inflammatory mechanisms of neurodegeneration in glaucoma with emphasis on potential immunomodulation strategies. Recent Findings Glaucomatous retina and optic nerve present multiple evidences of inflammatory responses of astroglia, microglia, and blood-borne immune cells. Although adaptive/protective responses of resident or systemic immune cells can support neurons and promote tissue repair mechanisms after injurious insults, prolonged inflammatory processes can also produce neurotoxic mediators. Treatments targeting these neurodestructive outcomes may restore immune homeostasis and protect neurons from inflammatory injury. Due to widespread and chronic nature of neuroinflammation in glaucoma, immunomodulation offers a treatment strategy to protect different neuronal compartments of RGCs during the chronic and asynchronous course of neurodegeneration. Uncovering of distinct molecular responses and interactions of different immune cells that determine the neuroinflammatory phenotype and participate in neurodegenerative outcomes will be critical to develop effective strategies for immunomodulation in glaucoma. Summary Neuroinflammation has increasingly been recognized to play an important role in glaucomatous neurodegeneration, and its modulation appears to be a promising treatment strategy for neuroprotection.

Neuroinflammatory Mechanisms of Mitochondrial Dysfunction and Neurodegeneration in Glaucoma

“…A proinflammatory signature acquired by astrocytes upon stress signals may, therefore, lead to tissue destruction and RGC death [ 146 , 147 ]. Along with the capacity to trigger innate immunity signaling pathways, reactive astroglia may also compromise the blood-retina barrier, which further increases the access of systemic immune cells into the retina and the optic nerve [ 137 , 145 ].…”

“…In line with these results, a longitudinal study revealed a gradual increment of serum autoantibodies in glaucoma patients with optic disc hemorrhages and no detectable change in patients with no optic disc hemorrhages [ 217 ]. In addition, the transfer of mononuclear cells from patients with optic disc hemorrhages into immune-deficient mice resulted in increased RGC loss [ 145 , 217 ]. The tracing of circulating monocytes with an inflammatory profile in the DBA/2J model confirmed the entry of these cells into the ONH and its contribution to glaucomatous damage [ 17 ].…”

“…Sun et al demonstrated that a brief period of ocular hypertension may be sufficient to initiate astroglial reactivity in experimental glaucoma [144]. is activation, seen in early stages of the disease, is characterized by morphological alterations and molecular responses that may be detectable even before the damage of RGCs and axons [145]. Although gliosis has the primary aim of circumscribing injured tissues to protect uninjured neurons, astroglial activation may lead to tissue remodeling that result in further biomechanical stress on optic nerve axons and in inadequate metabolic support to RGCs [143][144][145].…”

“…is activation, seen in early stages of the disease, is characterized by morphological alterations and molecular responses that may be detectable even before the damage of RGCs and axons [145]. Although gliosis has the primary aim of circumscribing injured tissues to protect uninjured neurons, astroglial activation may lead to tissue remodeling that result in further biomechanical stress on optic nerve axons and in inadequate metabolic support to RGCs [143][144][145]. A proinflammatory signature acquired by astrocytes upon stress signals may, therefore, lead to tissue destruction and RGC death [146,147].…”

New perspectives of immunomodulation and neuroprotection in glaucoma

“…The microglia and macroglia are involved in inflammatory responses to the injury signal. The proinflammatory cytokines exert an immunostimulatory effect and favor the interaction of glia with T lymphocytes, which are known for their neurodegenerative potential [ 28 , 29 ].…”