Eyeballing cholesterol efflux and macrophage function in disease pathogenesis

Abstract

Disorders of lipid metabolism are strongly associated with cardiovascular disease. Recently, there has been significant focus on how tissues process lipid deposits. Impaired cholesterol efflux has been shown to be crucial in mediating lipid deposition in atherosclerosis. The inability of macrophages to effectively efflux cholesterol from tissues initiates inflammation, plaque neovascularization, and subsequent rupture. Recent studies suggest that inability to effectively efflux cholesterol from tissues may have global implications far beyond atherosclerosis, extending to the pathophysiology of unrelated diseases. We examine the unifying mechanisms by which impaired cholesterol efflux facilitates tissue-specific inflammation and disease progression in age-related macular degeneration (AMD), a blinding eye disease, and in atherosclerosis, a disease associated with significant cardiovascular morbidity.

Keywords: AMD; atherosclerosis; cholesterol efflux; lipids; macrophage.

Figure 1. Clinical features of AMD

(a) Fundus photograph of the retina of a patient with dry AMD demonstrates large lipid laden drusen (arrowhead) underneath the retina. (b) Corresponding optical coherent tomography (OCT) of the central retina (macula) confirmed the presence of multiple drusen (arrowheads) underneath the retinal pigment epithelium layer (RPE-arrow). (c) Fundus photograph of a patient with the wet form of AMD illustrate subretinal hemorrhage and fluid (arrowhead) secondary to choroidal neovascularization (CNV, dotted circle). A fluorescein angiogram demonstrates leakage of dye from the CNV (arrow).

Figure 2. The central role of macrophage-mediated immunity in disease pathogenesis of AMD

Under baseline conditions, non-polarized macrophages (M0) traffic through the choriocapillaris underneath the retina sampling the tissue microenvironment. Aging and complex genetic factors impair macrophage function including reverse cholesterol transport (RCT) and lead to the deposition of lipid rich drusen underneath the retina and RPE in non-neovascular (dry) AMD. In dry AMD, dysfunctional classically activated macrophages (M1) can also induce inflammation driven cell death that leads to advanced stages of dry AMD characterized by loss of RPE cells, called geographic atrophy (GA) and subsequent loss of rod and cone photoreceptor neurons (PR). In the more aggressive form of disease, impaired macrophage RCT in the drusen rich sub-retinal micromilieu polarizes these cells to an alternatively activated (M2) phenotype. Alternatively activated macrophages are disease promoting and pro-angiogenic and facilitate the development of CNV. The sine qua non of wet AMD is the development of CNV, characterized by the growth of new blood vessels from the choroid into the sub-retinal space. These neovascular complexes are leaky and lead to exudation and hemorrhage with disruption of the retinal architecture, interference with the central visual axis, loss of PR and ultimately, irreversible vision loss.

Figure 3. Drusen composition and similarities with atherosclerotic plaques

Analysis of the composition of lipid-rich deposits (yellow) in drusen underneath the retina (left upper panel), or within atherosclerotic plaques (right upper panel) demonstrates similar constituents. Many complement proteins have been identified in drusen and atherosclerotic plaque suggesting an activation of the complement pathway within the deposits. Vitronectin, amyloid component, fibrinogen, clusterin and tissue inhibitor of metalloproteinase 3 (TIMP-3) are molecular constituents of both drusen and atherosclerotic plaques. In contrast, serum albumin and crystallins proteins are exclusive drusen components. ApoB lipoproteins are major constituents of drusen and atherosclerotic plaques. In addition to the plasma, the apoB deposited in drusen also have an intraocular source. Lipid profiling of drusen and atherosclerotic plaques revealed that they both contain esterified and unesterified cholesterol, fatty acids and phosphatidylcholine.