Contribution of microglia and monocytes to the development and progression of age related macular degeneration

Abstract

Purpose Age related macular degeneration (AMD) is the leading cause of irreversible vision loss in industrialised nations. Based on genetics, as well as proteome analysis of drusen, the role the innate immune system in the development and/or progression of the disease is well established. Mononuclear phagocytes, such as microglia and monocytes, play critical roles in innate immunity. Here, the role of retinal microglia in mediating normal retinal function, and how these cells change with age is discussed, so as to understand their role in the development and progression of AMD. Recent findings It is now known that microglia dynamically survey the neural environment, responding rapidly to even the most subtle neural injury. The dynamic and phagocytic roles of microglia can change with age contributing to alteration in the response of these cells to damage with age. Accumulation of innate immune cells in the subretinal space is a hallmark feature of the development of AMD, reflecting either an increase in migration of monocytes into the retina, or a failure of immune cell elimination from the retina. Furthermore, changes in phagocytic ability of immune cells could contribute to the accumulation of drusen deposits in the posterior eye. Summary An overview of how retinal microglia maintain retinal homeostasis under normal conditions is provided, and then how they contribute to each stage of AMD. In addition, circulating monocytes are altered in those with AMD, contributing to the overall inflammatory state. Understanding the role of cells of the innate immune system in AMD may uncover novel therapeutic targets with which to reduce either the development or progression of disease.

The Role of Inflammation in Age-Related Macular Degeneration

“…A hallmark of AMD development is the recruitment of the innate immune cells in the subretinal area with age [95]. The resident immune cells are the microglia in the retina, similar to tissue macrophages, which maintain normal retinal function, including the monitor and phagocytosis of damaged cell components [96].…”

“…The resident immune cells are the microglia in the retina, similar to tissue macrophages, which maintain normal retinal function, including the monitor and phagocytosis of damaged cell components [96]. Senescent microglia respond slowly to the injury and microglial dysfunction is a key factor in early AMD [95]. When retinal microglia migrate to the subretinal space, they may cause obvious changes in RPE cells, including further accumulation of microglia, increasing inflammation in the outer layer of the retina, and contributing to the formation of new blood vessels in wet AMD [97].…”

Ccr2 suppression by minocycline in Cx3cr1/Ccr2-visualized inherited retinal degeneration

“…Two potential mechanisms have been suggested that include action through its anti-apoptotic properties and anti-inflammatory effect (11). The innate immune system, which has a rapid non-specific response to an antigen, has been implicated in the development of retinal degeneration including human AMD and RP (12). In healthy retina, microglia are located in the outer and inner plexiform layers and survey retinal homeostasis like guardians of the retina (12).…”

“…The innate immune system, which has a rapid non-specific response to an antigen, has been implicated in the development of retinal degeneration including human AMD and RP (12). In healthy retina, microglia are located in the outer and inner plexiform layers and survey retinal homeostasis like guardians of the retina (12). However, in the stage of retinal degeneration, microglia get activated and migrate to outer retina and subretinal space, the space between the outer segments of photoreceptors and retinal pigment epithelium (RPE).…”

Inflammatory modulation in microglia: macropinocytosis for receptor trafficking and signalling

“…Activated microglia upregulate internalisation and lysosomal acidification for the clearance of undegraded or misfolded proteins, some of which go on to form pathognomonic plaques and amyloid-b fibrils in neurodegenerative diseases (Majumdar et al, 2007, Iribarren et al, 2005, Lai and McLaurin, 2012. Microglia are also implicated in other age-linked degenerative diseases such as age related macular degeneration (AMD) (Fletcher, 2020). Studies show that with age, microglia are less capable and slower in responding to injury but also present an increased inflammatory status that is prolonged and more difficult to resolve (Damani et al, 2011, Norden and Godbout, 2013, Von Bernhardi et al, 2015.…”