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

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.

Microglia: Key Players in Retinal Ageing and Neurodegeneration

“…Additionally, TSC2 –/– mice were found with reduced expression of complement protein C3, compared to TSC2 +/+ whilst TSC2 –/– also had reduced phagocytic activity of RPE compared to controls and TSC1 –/– ( Cheng et al, 2021 ). Although C3 has been associated with microglial phagocytosis ( Borucki et al, 2020 ), this particular observation in this study was not made exclusively in microglial phagocytosis ( Cheng et al, 2021 ). Overall, TSC-mediated clinically translatable AMD GA pathology may be associated with observations of retinal amoeboid microglia, reduced C3 expression, and reduced ability to clear RPE debris by phagocytosis.…”

“…AMD affects the central macular region of the retina, resulting in abnormalities of the structural and molecular composition of photoreceptor (PR), retinal pigment epithelium (RPE), Bruch’s membrane, and choriocapillaris ( Chirco et al, 2016 ). Early AMD is characterised by yellow drusen, which are composed of proteins and lipids such as lipofuscin and Aβ peptides ( Wu et al, 2021 ), that lie within or beneath the RPE ( Silverman and Wong, 2018 ), and RPE and photoreceptor degeneration ( Borucki et al, 2020 ). The disease may progress to later stages, broadly defined by two types: dry AMD advancing to geographic atrophy (GA) ( Waugh et al, 2018 ) or wet AMD characterized by choroidal neovascularisation (CNV) ( Silverman and Wong, 2018 ).…”

Efferocytosis in multisystem diseases (Review)

“…The protein CCN1 is a critical opsonin in skin injury by acting as a bridging molecule in neutrophil efferocytosis ( 178 ). Abnormal activation of complement-mediated phagocytosis also affects retinal diseases, such as glaucoma and age-related macular degeneration ( 179 ). C1q is found to stimulate endothelial cells proliferation and migration and to promote tube formation and sprouting of new vessels ( 180 ).…”

Sterile Injury Repair and Adhesion Formation at Serosal Surfaces

“…This synapse is mediated by complement and complement receptors expressed by phagocytes (92). There is increased interest in studying the role of natural IgM, and IgM-dependent, complement-mediated phagocytosis in several disease models (93)(94)(95). Although available data is limited, it is conceivable that complement and natural antibodies of body cavities play an important a role in wound repair at serosal surfaces.…”