Retinal Ganglion Cell Survival and Axon Regeneration after Optic Nerve Injury: Role of Inflammation and Other Factors

Abstract

The optic nerve, like most pathways in the mature central nervous system, cannot regenerate if injured, and within days, retinal ganglion cells (RGCs), the neurons that extend axons through the optic nerve, begin to die. Thus, there are few clinical options to improve vision after traumatic or ischemic optic nerve injury or in neurodegenerative diseases such as glaucoma, dominant optic neuropathy, or optic pathway gliomas. Research over the past two decades has identified several strategies to enable RGCs to regenerate axons the entire length of the optic nerve, in some cases leading to modest reinnervation of di- and mesencephalic visual relay centers. This review primarily focuses on the role of the innate immune system in improving RGC survival and axon regeneration, and its synergy with manipulations of signal transduction pathways, transcription factors, and cell-extrinsic suppressors of axon growth. Research in this field provides hope that clinically effective strategies to improve vision in patients with currently untreatable losses could become a reality in 5–10 years.

Aldose reductase inhibition decelerates optic nerve degeneration by alleviating retinal microglia activation

“…Interestingly, neuroprotection was not observed in an animal microglia depletion model (using stimulating factor 1 receptor inhibitor PLX5622) 51 , which might be because deletion of microglia might eliminate both detrimental and neuroprotective effects in the retina. However, growing evidence shows that microglia modulation has been reported to inhibit disease progression 1 , 34 , 52 . Thus, we hypothesize that AR inhibition protects RGCs from death by suppressing microglia (or macrophage) activation.…”

“…An increase in the AR polyol pathway enhances the production of cytokines/chemokines and ROS, leading to the NADH/NAD + redox imbalance in various inflammatory diseases 29 , 31 – 33 . As ocular inflammation is a direct feature of ocular neuropathies, modulating the immune response is vital to promote axonal growth 1 , 34 . Under normoglycemic conditions, AR inhibition suppresses inflammatory signaling via an alternative mechanism.…”

Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair

“…Research over the past two decades has identified several strategies to enable RGCs to regenerate axons the entire length of the optic nerve, in some cases leading to modest reinnervation of di- and mesencephalic visual relay centers. A review by Wong and Benowitz [ 2 ] primarily focuses on the role of the innate immune system in improving RGC survival and axon regeneration, and its synergy with manipulations of signal transduction pathways, transcription factors, and cell-extrinsic suppressors of axon growth. Research in this field hopefully will identify clinically effective strategies to improve vision in patients with currently untreatable losses within 5–10 years.…”

Immune stimulation recruits a subset of pro-regenerative macrophages to the retina that promotes axonal regrowth of injured neurons

“…Over the past decades, multiple studies, using the retinofugal pathway and the optic nerve crush (ONC) paradigm as a neurodegeneration model, have shown that induction of controlled inflammation in the retina induces retinal ganglion cell (RGC) survival and axonal regrowth in rodents [ 26 – 32 ]. Previous research revealed that an inflammatory stimulation results in infiltration of neutrophils and MDMs in both the vitreous and retina and leads to modulation of resident macrophages, as well as retinal astrocytes and Müller glia [ 33 , 34 ]. While it is established that an acute inflammatory response is beneficial for survival and axonal regrowth of damaged RGCs, controversy still prevails about which cells, cell states, molecules and pathways are functionally implicated.…”