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.

Keywords: age-related macular degeneration; complement; glaucoma; lateral geniculate nucleus; multiple sclerosis; phagocytosis; retina; synapse.

Figure 1

Overview of the visual system. (A) Layers of the retina: ILM, inner limiting membrane; NFL, nerve fiber layer; GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; PL, photoreceptor layer; RPE, retinal pigment epithelium. Connections and cell types are explained in the text. (B) Connectivity of the visual system: eye (1), optic nerve (2), optic chiasm (3), optic tract (4), lateral geniculate nucleus (5), optic radiation (6), primary visual cortex (7).

Figure 2

Overview of the complement system. There are three main complement activation pathways: the classical (top), lectin (middle), and alternative (bottom). All of these pathways lead to the cleavage of C3 and subsequently C5, leading to the opsonization of tissues (by C3b, iC3b, and C3d), the production of anaphylatoxins (C3a and C5a), and the assembly of the cytolytic membrane attack complex (C5b-9).