Not All Stressors Are Equal: Mechanism of Stressors on RPE Cell Degeneration

Abstract

Age-related macular degeneration (AMD) is a major cause of irreversible blindness among the elderly population. Dysfunction and degeneration of the retinal pigment epithelial (RPE) layer in the retina underscore the pathogenesis of both dry and wet AMD. Advanced age, cigarette smoke and genetic factors have been found to be the prominent risk factors for AMD, which point to an important role for oxidative stress and aging in AMD pathogenesis. However, the mechanisms whereby oxidative stress and aging lead to RPE cell degeneration are still unclear. As cell senescence and cell death are the major outcomes from oxidative stress and aging, here we review the mechanisms of RPE cell senescence and different kinds of cell death, including apoptosis, necroptosis, pyroptosis, ferroptosis, with an aim to clarify how RPE cell degeneration could occur in response to AMD-related stresses, including H₂O₂, 4-Hydroxynonenal (4-HNE), N-retinylidene-N-retinyl-ethanolamine (A2E), Alu RNA and amyloid β (Aβ). Besides those, sodium iodate (NaIO₃) induced RPE cell degeneration is also discussed in this review. Although NaIO₃ itself is not related to AMD, this line of study would help understand the mechanism of RPE degeneration.

Keywords: AMD; RPE; cell death; oxidative stress; senescence.

FIGURE 1

Oxidative stress accumulation increases while antioxidative capability decreases in cells during aging. Cells could survive when oxidative stress is balanced by antioxidative systems while senescence could occur under mild oxidative stress and cell death could happen under more severe oxidative stress.

FIGURE 2

Overview of cell death pathways. Apoptosis is triggered by either intrinsic (by UV, radiation, exogenous ROS, or ER stress) or extrinsic signals (through FasL/Fas or TNF/TNFR) and is regulated by the caspase family of proteins. Caspase 4, 9, and 8/10 serve as initiator caspase, while Caspase 3/6/7 serve as executor caspase. Necroptosis is initiated by activation of TNFR and subsequent activation of necrosome containing phosphorylated RIPK1 and RIPK3, phosphorylation and oligomerization of MLKL then result in cell rupture, death and HMGB1 release. Pyroptosis is induced through both Caspase-1 and Caspase-4 activation which induce GSDMD cleavage, followed by oligomerization of N terminal of GSDMD which then leads to cell rupture and death. Caspase 1 cleaves IL-1β and IL-18, leading to its activation and release from the cells. Ferroptosis is induced by the inhibition of system Xc and is featured by accumulation of lipid ROS which can be inhibited by GPX4 and FSP1. Irons are transferred through transferrin and its receptor and are involved in the Fenton reaction leading to lipid peroxidation. ER, Endoplasmic reticulum; UV, Ultraviolet light; TNF/TNFR, Tumor necrosis factor/Tumor necrosis factor receptor; RIPK3, Receptor-interacting protein kinase 3; MLKL, Mixed Lineage Kinase Domain Like Pseudokinase; HMGB1, High mobility group box 1; ASC, Apoptosis-associated speck-like protein containing a caspase recruitment domain; LPS, Lipopolysaccharide; N-GSDMD, N terminal of gasdermin D; C-GSDMD, C terminal of gasdermin D; IL-1β, Interleukin-1β; IL-18, Interleukin-18; GSH, Glutathione; GPX4, Glutathione Peroxidase 4; FSP1, Ferroptosis suppressor protein 1; ROS, Reactive oxygen species.