Neuroinflammation, Microglia and Implications for Retinal Ganglion Cell Survival and Axon Regeneration in Traumatic Optic Neuropathy

Abstract

Traumatic optic neuropathy (TON) refers to a pathological condition caused by a direct or indirect insult to the optic nerves, which often leads to a partial or permanent vision deficit due to the massive loss of retinal ganglion cells (RGCs) and their axonal fibers. Retinal microglia are immune-competent cells residing in the retina. In rodent models of optic nerve crush (ONC) injury, resident retinal microglia gradually become activated, form end-to-end alignments in the vicinity of degenerating RGC axons, and actively internalized them. Some activated microglia adopt an amoeboid morphology that engulf dying RGCs after ONC. In the injured optic nerve, the activated microglia contribute to the myelin debris clearance at the lesion site. However, phagocytic capacity of resident retinal microglia is extremely poor and therefore the clearance of cellular and myelin debris is largely ineffective. The presence of growth-inhibitory myelin debris and glial scar formed by reactive astrocytes inhibit the regeneration of RGC axons, which accounts for the poor visual function recovery in patients with TON. In this Review, we summarize the current understanding of resident retinal microglia in RGC survival and axon regeneration after ONC. Resident retinal microglia play a key role in facilitating Wallerian degeneration and the subsequent axon regeneration after ONC. However, they are also responsible for producing pro-inflammatory cytokines, chemokines, and reactive oxygen species that possess neurotoxic effects on RGCs. Intraocular inflammation triggers a massive influx of blood-borne myeloid cells which produce oncomodulin to promote RGC survival and axon regeneration. However, intraocular inflammation induces chronic neuroinflammation which exacerbates secondary tissue damages and limits visual function recovery after ONC. Activated retinal microglia is required for the proliferation of oligodendrocyte precursor cells (OPCs); however, sustained activation of retinal microglia suppress the differentiation of OPCs into mature oligodendrocytes for remyelination after injury. Collectively, controlled activation of retinal microglia and infiltrating myeloid cells facilitate axon regeneration and nerve repair. Recent advance in single-cell RNA-sequencing and identification of microglia-specific markers could improve our understanding on microglial biology and to facilitate the development of novel therapeutic strategies aiming to switch resident retinal microglia’s phenotype to foster neuroprotection.

High-Mobility Group Box 1 Inhibitor BoxA Alleviates Neuroinflammation-Induced Retinal Ganglion Cell Damage in Traumatic Optic Neuropathy

“…Therefore, we speculated whether the HMGB1 inhibitor BoxA could inhibit the activation of microglia after ONC. In most cases, ionized calcium-binding adapter molecule 1 (Iba1) can be used to differentiate microglia from other cells [ 13 ]. In the ONC + PBS group, Iba1 (+) cells were mainly distributed in the ganglion cell layer, inner plexiform layer, inner nuclear layer, and outer plexiform layer ( p < 0.05).…”

“…Optic nerve crush (ONC) is a well-validated model of TON [ 12 ]. Researchers found that ONC activates retinal microglia and the recruitment of infiltrating macrophages into the retina [ 13 ]. Microglia are the resident immune cells of the central nervous system and the primary initiators of neuroinflammation [ 14 ].…”

Functional and Phenotypic Diversity of Microglia: Implication for Microglia-Based Therapies for Alzheimer’s Disease

“…Over the past decades, much effort has been attributed to characterize ramified (resting) and amoeboid (activated) microglia in various neurological disorders that might be an oversimplification. Apart from the classical subdivision of microglia into ramified and amoeboid microglia, bipolar/rod-shaped microglia also appeared in the brains under several pathological conditions ( Ziebell et al, 2012 ; Taylor et al, 2014 ; Au and Ma, 2017 , 2022 ; Bachstetter et al, 2017 ; Edler et al, 2018 ; Holloway et al, 2020 ). In fact, bipolar/rod-shaped microglia was the first form of activated microglia characterized by Nissl in 1899 ( Nissl, 1899 ).…”

“…Microglia are morphologically diverse innate immune cells that are originated from primitive myeloid precursors in the embryonic yolk sac ( Ginhoux et al, 2010 ), which account for approximately 5–12% of the total cell population in the mammalian brain ( Dos Santos et al, 2020 ). As an important player for maintaining homeostasis within the CNS throughout the lifetime, microglia are involved in multiple vital cellular processes including immune surveillance, antigen presentation, debris clearance, neuronal apoptosis, maintenance of synaptic activity, and production of cytokine, chemokine and neurotrophic factors ( Tam and Ma, 2014 ; Heneka et al, 2015 ; Ransohoff, 2016a ; Tam et al, 2016 ; Au and Ma, 2017 , 2022 ). Impaired microglial function is often associated with various neurodegenerative diseases such as AD ( Leng and Edison, 2021 ).…”

Immune modulating nanoparticles for the treatment of ocular diseases

“…Moreover, microglia can also promote Wallerian degeneration and axon regeneration. Nevertheless, when microglia and macrophages are depleted, neuron loss is inevitable [121,122]. At the same time, microglia can also produce cytokines, chemokines and ROS, which have neurotoxic effects on RGCs.…”