Understanding the role of microglia in the onset of photoreceptor degeneration

Abstract

AbstractPhotoreceptor degenerative diseases are currently the leading cause of irreversible blindness in developed countries and a major cause of irreversible blindness in the world. The most common forms of these diseases are age‐related macular degeneration and retinitis pigmentosa, both diseases cause a profound visual impairment due to photoreceptor loss. In the early stages of photoreceptor degeneration, glial cells have a major role to play, presumably leading to extensive retinal remodelling. The mammalian retina contains three types of glial cells. Two types of macroglial cells: astrocytes and Müller cells, and microglial cells. Microglial cells are the major resident immune cells in the retina and, although these cells and neuroinflammation have been implicated in the pathology of many neurodegenerative diseases, their role and function in photoreceptor degenerations are not yet fully understood. During retinal degeneration, microglial cells change their morphology, become activated and travel from the inner to the outer layers of the retina to phagocytose the dying photoreceptors, while astrocytes and Müller cells become hypertrophic, and overexpress glial fibrillary acidic protein (GFAP) filling the space left by dead photoreceptors to form a glial seal. It is known that activated microglial cells can be either neuroprotective or neurodestructive during photoreceptor degenerations, and therefore it is not yet clear whether activated microglial cells may increase or decrease photoreceptor loss. Microglial cell activation, migration and proliferation occur simultaneously with the onset of photoreceptor degeneration, prior to the loss of the vast majority of photoreceptors. During photoreceptor loss, microglial cells reach the outer nuclear and outer segment layers. These events suggest that photoreceptor death is the trigger for the activation and migration of microglia to the outer retinal layers, where they phagocytose the dying photoreceptors and remove cellular debris. By carrying out these functions, microglial cells in the retina may affect photoreceptor survival or death, eventually phagocytizing stressed but still viable photoreceptors. Interestingly, inhibition of microglial cell activation and migration during photoreceptor degeneration results in improved cone outer segment morphology and increased photoreceptor survival, which suggest that the role of activated microglial cells may be more neurodestructive than neuroprotective and that treatments with anti‐inflammatory drugs that modulate microglial reactivity may be considered in the early stages of photoreceptor degenerations.