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.

Keywords: Müller cell; astrocyte; microglia; neuroinflammation; optic neuropathy; retinal degeneration.

Figure 1

Inflammatory responses after optic nerve crush (ONC) injury. (A) In the intact retina, retinal microglia usually resided in NFL, GCL, IPL, INL, and OPL. These resident retinal microglia adopt ramified morphology with which they constantly send and withdraw their processes to sense the surrounding microenvironment. Retinal astrocytes and Müller cells are the two major macroglial cells that resided in retinae for the maintenance of retinal homeostasis. (B) Optic nerve crush (ONC) triggers the activation of resident retinal microglia, as well as retinal astrocytes and Müller cells. Some of the microglia transform into bipolar/rod-shaped microglia and colonize adjacent to the degenerating RGC axons in NFL. These bipolar/rod-shaped microglia actively internalized these degenerating axons after ONC. Some activated microglia adopt amoeboid morphology and actively engulf the dead RGCs in GCL. Also, these activated retinal microglia produce a broad spectrum of pro-inflammatory cytokines (e.g. IL-1β, IL-6 and TNF-α), chemokines (CCL2, CCL3 and CCL5), and reactive oxygen species (ROS), which induced reactive astrocytes to adopt a neurotoxic A1 phenotype and increased production of neurotoxic factors. Activated Müller cells are also responsible for the production of pro-inflammatory cytokines in the injured retinae. Collectively, the number of survived RGCs gradually declined over time, and most of these survived RGCs failed to regenerate across the lesion site, leading to a permanent vision loss after ONC. (C) Intraocular inflammation induced by zymosan or curdlan treatment, or lens injury triggers a massive influx of blood-borne myeloid cells, and robust astrocyte and Müller cell activation. The infiltrating myeloid cells produce a large quantity of growth-promoting factors, such as oncomodulin, which promoted RGC survival after ONC. The reactive astrocytes also elevate the production of CNTF and LIF after intraocular inflammation. More importantly, the macrophage- and astrocyte-derived growth-promoting factors stimulate robust axon regeneration which enabled a partial restoration of some visual-guided behaviors when combined with other manipulations, such as PTEN deletion. NFL, nerve fibre layer; GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; PRL, photoreceptor layer; RPE, retinal pigment epithelium; RGC, retinal ganglion cell; ROS, reactive oxygen species. CNTF, ciliary neurotrophic factor; LIF, leukemia inhibitory factor.