Microglia: Key Players in Retinal Ageing and Neurodegeneration

Abstract

Microglia are the resident immune cells of the central nervous system (CNS) and play a key role in maintaining the normal function of the retina and brain. During early development, microglia migrate into the retina, transform into a highly ramified phenotype, and scan their environment constantly. Microglia can be activated by any homeostatic disturbance that may endanger neurons and threaten tissue integrity. Once activated, the young microglia exhibit a high diversity in their phenotypes as well as their functions, which relate to either beneficial or harmful consequences. Microglial activation is associated with the release of cytokines, chemokines, and growth factors that can determine pathological outcomes. As the professional phagocytes in the retina, microglia are responsible for the clearance of pathogens, dead cells, and protein aggregates. However, their phenotypic diversity and phagocytic capacity is compromised with ageing. This may result in the accumulation of protein aggregates and myelin debris leading to retinal neuroinflammation and neurodegeneration. In this review, we describe microglial phenotypes and functions in the context of the young and ageing retina, and the mechanisms underlying changes in ageing. Additionally, we review microglia-mediated retinal neuroinflammation and discuss the mechanisms of microglial involvement in retinal neurodegenerative diseases.

Keywords: ageing; microglia; morphology; phagocytosis; phenotypes; retina; retinal neurodegenerative disease.

FIGURE 1

Schematic representation of microglial distribution in layers of normal mature retina. As development progresses, microglia migrate from the GCL and IPL towards the outer layers of the retina (yellow arrow). In the young retina, the number of microglia in their ramified appearance is found predominantly in the synaptic layers: the OPL and IPL. They can also be found in lesser numbers in the GCL and INL. However, no microglia are found in the ONL, a specialised microglial exclusion zone. The concentration of microglial processes in the plexiform layers facilitates frequent and dynamic contact with neuronal dendrites, axons, and synapses. The ramified morphology allows microglia to constantly extend and retract their processes. Together, these features facilitate constant surveillance of the surrounding microenvironment. ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer; RNFL, retinal nerve fibre layer.

FIGURE 2

Diagram of microglial morphologies. (A) Microglial morphology varies based on activation state, in response to changing environmental conditions. Arrows demonstrate possible transitions between states. These transitions can occur in both directions, allowing microglia to switch back and forth between activation states. (a) Microglia under resting physiological conditions have a ramified appearance. (b) Disruption to environmental homeostasis leads them to elongate their processes and transiently exhibit a hyper-ramified state. (c) In response to considerable environmental damage, they rapidly adopt an activated morphology, with an increased soma size, and thicker, shorter processes. (d) Substantial insult leads them to adopt an amoeboid appearance, with complete retraction of processes, allowing directed motility and phagocytosis of target material. (e) Rod microglia, which are specifically associated with retinal neurodegeneration, exhibit a uniquely narrow and elongated morphology, with few processes. It is unclear which microglial activation state(s) give(s) rise to rod microglia. Figure based on Holloway (Holloway et al., 2019). (B) Different predominant morphologies and activation states of microglia may be found in the young, ageing, and neurodegenerative retina. Generally, ramified microglia may be predominantly found in the young retina. In the ageing retina, the reactive/activated and amoeboid microglia are predominantly found. In cases of retinal neurodegenerative disease, reactive/activated, amoeboid, and rod microglia are predominantly found. Blue microglia are illustrative representations to demonstrate morphological changes. Green microglia are from whole-mount retinal images of Iba-1 stained C57BL6 mice, obtained from the Cordeiro laboratory. Scale bar = 50 μm.