Progress and perspectives on the role of RPE cell inflammatory responses in the development of age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. The etiology of AMD remains poorly understood and no treatment is currently available for the atrophic form of AMD. Atrophic AMD has been proposed to involve abnormalities of the retinal pigment epithelium (RPE), which lies beneath the photoreceptor cells and normally provides critical metabolic support to these light-sensing cells. Cumulative oxidative stress and local inflammation are thought to represent pathological processes involved in the etiology of atrophic AMD. Studies of tissue culture and animal models reveal that oxidative stress-induced injury to the RPE results in a chronic inflammatory response, drusen formation, and RPE atrophy. RPE degeneration in turn causes a progressive degeneration of photoreceptors, leading to the irreversible loss of vision. This review describes some of the potential major molecular and cellular events contributing to RPE death and inflammatory responses. In addition, potential target areas for therapeutic intervention will be discussed and new experimental therapeutic strategies for atrophic AMD will be presented.

Keywords: age-related macular degeneration; complement; danger signals; inflammation; retinal pigment epithelial cells.

Figure 1

Conditions that trigger retinal pigment epithelial (RPE) cell injury and subsequent release of damage-associated molecule pattern (DAMP) molecules. RPE cell injury is triggered by environmental stress, metabolic stress, and complement attack. Injured or dying RPE cells then produce danger signals that are defined as DAMP molecules. Some of these danger signals are intracellular molecules and others are the cleaved products of extracellular components such as extracellular matrix (ECM). Abbreviations: HMGB1, high mobility group box 1; HSPs, heat-shock proteins; MMPs, matrix metalloproteinases.

Figure 2

Receptors that sense danger signals released from neighboring injured retinal pigment epithelial (RPE) cells. Toll-like receptors (TLRs) and the receptor for AGE (RAGE) can detect danger signals released from or generated by dying RPE cells. Once stimulated, TLRs and RAGE activate the transcription factor nuclear factor kappa B (NFkB), thereby turning on the transcription of many pro-inflammatory genes and consequently inducing an inflammatory response. The DAMP molecules ATP and monosodium urate stimulate a pathway that works through Nod-like receptor NACHT, LRR, and PYD containing protein-3 (NALP3) and leads to the production of the proinflammatory cytokine interleukin-1β (IL-1β) and IL-18. Those pathways surrounded by dotted lines indicate a current lack of data supporting a functional pathway in RPE cells. Abbreviations: AGE, advanced glycation endproducts; OxLDL, oxidized low density proteins.