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.

Keywords: age-related macular degeneration (AMD); apoptosis; autophagy; cytokine; inflammasome; macrophage; microglia; necroptosis; pyroptosis.

Figure 1

Electron micrographs showing pyroptosis in mouse retinal stem cells (RSC) in response to in vitro application of IL-1β and IL-18 (A). IL-1β induced mitochondrial (M) damage, autophagy (A), glycogen accumulation (not labeled), lipid droplets (L), and nuclear condensation (N); (B) IL-1β induced advanced disintegration of cytoplasm in RSCs; (C) IL-18 induced mitochondrial (M) damage and autophagy (A); (D) IL-18 induced advanced cytoplasmic disintegration and nuclear condensation (N).

Figure 2

Electron micrograph showing the effects of in vitro application of IL-17 to ARPE-19 cells. IL-17 induced mitochondrial (M) damage as well as autophagosome (A) formation. Nuclear membrane appears compromised (N), chromatin is diffused and heterochromatin distributed along the nuclear membrane. Lipid droplets (L) are observed in the cytoplasm.

Figure 3

Electron micrograph from a patient with advanced AMD showing extranuclear DNA. Extranuclear chromatin (C) and mitochondrial disintegration (M) is observed. Chromatin strands form vesicles that clump together to form a lattice.