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Inflammation and Cell Death in Age-Related Macular Degeneration: An Immunopathological and Ultrastructural Model.

ABSTRACT: The etiology of Age-related Macular Degeneration (AMD) remains elusive despite the characterization of many factors contributing to the disease in its late-stage phenotypes. AMD features an immune system in flux, as shown by changes in macrophage polarization with age, expression of cytokines and complement, microglial accumulation with age, etc. These point to an allostatic overload, possibly due to a breakdown in self vs. non-self when endogenous compounds and structures acquire the appearance of non-self over time. The result is inflammation and inflammation-mediated cell death. While it is clear that these processes ultimately result in degeneration of retinal pigment epithelium and photoreceptor, the prevalent type of cell death contributing to the various phenotypes is unknown. Both molecular studies as well as ultrastructural pathology suggest pyroptosis, and perhaps necroptosis, are the predominant mechanisms of cell death at play, with only minimal evidence for apoptosis. Herein, we attempt to reconcile those factors identified by experimental AMD models and integrate these data with pathology observed under the electron microscope-particularly observations of mitochondrial dysfunction, DNA leakage, autophagy, and cell death.

SUBMITTER: Ardeljan CP

PROVIDER: S-EPMC4287551 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Contrary to Alzheimer's disease (AD), the APOE2 allele increases and the APOE4 allele reduces the risk to develop age-related macular degeneration (AMD) compared with the most common APOE3 allele. The underlying mechanism for this association with AMD and the reason for the puzzling difference with AD are unknown. We previously demonstrated that pathogenic subretinal mononuclear phagocytes (MPs) accumulate in Cx3cr1-deficient mice due to the overexpression of APOE, interleukin-6, and CC chemokine ligand 2 (CCL2). We here show using targeted replacement mice expressing the human APOE isoforms (TRE2, TRE3, and TRE4) that MPs of TRE2 mice express increased levels of APOE, interleukin-6, and CCL2 and develop subretinal MP accumulation, photoreceptor degeneration, and exaggerated choroidal neovascularization similar to AMD. Pharmacological inhibition of the cytokine induction inhibited the pathogenic subretinal inflammation. In the context of APOE-dependent subretinal inflammation in Cx3cr1(GFP/GFP) mice, the APOE4 allele led to diminished APOE and CCL2 levels and protected Cx3cr1(GFP/GFP) mice against harmful subretinal MP accumulation observed in Cx3cr1(GFP/GFP)TRE3 mice. Our study shows that pathogenic subretinal inflammation is APOE isoform-dependent and provides the rationale for the previously unexplained implication of the APOE2 isoform as a risk factor and the APOE4 isoform as a protective factor in AMD pathogenesis.Significance statementThe understanding of how genetic predisposing factors, which play a major role in age-related macular degeneration (AMD), participate in its pathogenesis is an important clue to decipher the pathomechanism and develop efficient therapies. In this study, we used transgenic, targeted replacement mice that carry the three human APOE isoform-defining sequences at the mouse APOE chromosomal location and express the human APOE isoforms. Our study is the first to show how APOE2 provokes and APOE4 inhibits the cardinal AMD features, inflammation, degeneration, and exaggerated neovascularization. Our findings reflect the clinical association of the genetic predisposition that was recently confirmed in a major pooled analysis. They emphasize the role of APOE in inflammation and inflammation in AMD.

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Inflammation and Cell Death in Age-Related Macular Degeneration: An Immunopathological and Ultrastructural Model.

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