On phagocytes and macular degeneration

Abstract

Age related macular degeneration (AMD) is a complex multifactorial disease caused by the interplay of age and genetic and environmental risk factors. A common feature observed in early and both forms of late AMD is the breakdown of the physiologically immunosuppressive subretinal environment and the protracted accumulation of mononuclear phagocytes (MP). We here discuss the origin and nature of subretinal MPs, the mechanisms that lead to their accumulation, the inflammatory mediators they produce as well as the consequences of their chronic presence on photoreceptors, retinal pigment epithelium and choroid. Recent advances highlight how both genetic and environmental risk factors directly promote subretinal inflammation and tip the balance from a beneficial inflammation that helps control debris accumulation to detrimental chronic inflammation and destructive late AMD. Finally, we discuss how changes in life style or pharmacological intervention can help to break the vicious cycle of inflammation and degeneration, restore the immunosuppressive properties of the subretinal space, and reestablish homeostasis.

Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism

“…As the now avascular neural retina matures, increasing its metabolic demands, VEGF is secreted by the hypoxic neuroglia giving rise to pathological neovascularization (Joyal et al, 2012, 2015; Pierce et al, 1995; Pierce et al, 1996; Scott et al, 2010; Sitaras et al, 2015; Stone et al, 1995; Weidemann et al, 2010). Microglial cells also contribute to VEGF secretion and pathological angiogenesis, which is reviewed elsewhere (Binet and Sapieha, 2015; Guillonneau et al, 2017). Similarly in the outer retina, excessive expression of VEGF by photoreceptors and RPE contributes to the subretinal neovascularization that characterizes wet AMD, discussed in more detail later (Campochiaro, 2015; Grisanti and Tatar, 2008; Joyal et al, 2016; Ohno-Matsui et al, 2002; Witmer et al, 2003).…”

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

“…In the healthy retina, the insult is rapidly neutralized, the damaged tissue is repaired, and a return to homeostasis is achieved with only very little retinal remodeling (Chen et al, ). This finite microglial activation is beneficial since the toxicity associated with the immune response is outweighed by the toxicity produced due to the noxious insult (Guillonneau et al, ). However, under aggravated conditions owing to genetic predispositions or high glucose levels, microglial activation persists (Gupta et al, ; Omri et al, ).…”

“…Additionally, by the secretion of chemokines such as CCL2, microglia attract further phagocytes, which include infiltrating monocytes and choroidal macrophages due to the leakage of the BBB and the newly formed blood vessels (Caicedo et al, ; Sennlaub et al, ). Indeed, such changes in retinal microglia morphology, location, and infiltration of macrophages are common hallmarks of AMD, DR, and hereditary retinopathies (Fig ; Karlstetter et al, ; Guillonneau et al, ).…”

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

“…They remove inactive synapses during development and in the retina are important for mediating maturation of cones . Importantly, deficits in microglial function are thought to be an important factor in the development of early AMD . This review outlines the role of microglia in maintaining normal retinal function and how they may be important in the development of disease.…”

“…The importance of innate immunity in the development of AMD is exemplified by the accumulation of complement components within drusen deposits and also the widespread inheritance of mutations in genes affecting the complement system including single nucleotide polymorphisms in Complement Factors H, B and I as well as other components such as C3 . More recently, the cellular mediators of the innate immune system, especially mononuclear phagocytes, have been implicated in the development of AMD . Although they play critical roles in maintaining normal retinal function, they can change with age, genetics or disease .…”