Complement-Mediated Microglial Phagocytosis and Pathological Changes in the Development and Degeneration of the Visual System.

Davis M Borucki,Stephen Tomlinson,Amer Toutonji,Christine Couch,Baerbel Rohrer,Khalil Mallah

doi:10.3389/fimmu.2020.566892

Davis M Borucki, Stephen Tomlinson + Show 4 more

Open Access

https://doi.org/10.3389/fimmu.2020.566892

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Abstract

The focus of this review is the role of complement-mediated phagocytosis in retinal and neurological diseases affecting the visual system. Complement activation products opsonize synaptic material on neurons for phagocytic removal, which is a normal physiological process during development, but a pathological process in several neurodegenerative diseases and conditions. We discuss the role of complement in the refinement and elimination of synapses in the retina and lateral geniculate nucleus, both during development and in disease states. How complement and aberrant phagocytosis promotes injury to the visual system is discussed primarily in the context of multiple sclerosis, where it has been extensively studied, although the role of complement in visual dysfunction in other diseases such as stroke and traumatic brain injury is also highlighted. Retinal diseases are also covered, with a focus on glaucoma and age-related macular degeneration. Finally, we discuss the potential of complement inhibitory strategies to treat diseases affecting the visual system.

Highlights

The visual system is one of the best understood sensory/neural systems in terms of development and signal transduction and processing
The complement system has been implicated in several diseases of the retina, and for representation we focus here on only glaucoma and agerelated macular degeneration, in which complement has a firmly established role and in which complement-based therapeutics have shown efficacy
In certain disease states the complement system is aberrantly activated and contributes to opsonization of functional and/or salvageable synapses, leading to irreversible damage. We focus on these processes in the afferent visual system, the retina-lateral geniculate nucleus (LGN)-primary visual cortex axis, complement plays an active role in other regions of the brain in homeostasis and disease

Summary

INTRODUCTION

The visual system is one of the best understood sensory/neural systems in terms of development and signal transduction and processing. In the amyloid precursor protein (APP) transgenic mouse model of AD, eliminating C3 resulted in increased levels of Aβ and loss of neurons in the hippocampus, indicating a beneficial role for complement-mediated phagocytosis in tissue homeostasis [24] This is in contrast with findings in more recent animal studies showing that CR3 deficiency improves microglial clearance of Aβ in vivo and in vitro by increasing enzymatic degradation [25]. Another study, using the double transgenic human APP/PS1 (presenilin 1) AD model, shows that despite increased levels of cerebral Aβ upon elimination of C3, mice show better cognitive performance and fewer microglia around amyloid plaques along with reduced loss of neurons and synapses [26] Together, these seemingly contradictory findings could imply that C3 is important for the clearance of Aβ plaques, the effect of which depends on the presence of a mutant presenilin 1 (PS1) protein. This synaptic pruning process is caused by spontaneous retinal activity, which causes calcium influx that reinforces synaptic connections from

CONCLUSION

Findings

SIGNIFICANCE STATEMENT