Overview
There are two forms of late-stage age-related macular degeneration (AMD): dry and wet. About 8-9 in 10 people with AMD have the dry form (also called geographic atrophy). In dry AMD support cells in a layer of the eye called the retinal pigment epithelium die, followed by the death of light-sensitive ‘photoreceptor’ cells in the layer above the support cells. At the moment there is no treatment for dry AMD.
Research has found that a molecule known as IL-18 can cause dry AMD by killing retinal pigment epithelium cells. But IL-18 can prevent new blood vessels growing and unhealthy new blood vessel growth is what does the damage in wet AMD. So on one hand IL-18 protects and on the other it does damage. To add to the confusion, some people with dry AMD then develop the wet form. And some people with wet AMD can get the dry form after treatment to stop new blood vessels growing. So it’s really important to find out exactly what IL-18 does in the ageing eye.
In this project the team is working with mice that have a version of dry AMD. They’re studying the process (called autophagy) that cells use to recycle their own parts when they get damaged through everyday wear and tear and from AMD risk-factors such as smoking. They think that when autophagy goes wrong it sets off a chain of events that leads to more IL-18 being made, which in turn could trigger dry AMD. Results from the study could tell us whether it’s safe to increase IL-18 in people with dry AMD in order to prevent wet AMD from developing, something that has been suggested. And they may also give us new targets for future drug treatments for dry AMD.
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Scientific summary
Retinal pigment epithelial cell death in age-related macular degeneration: the link between autophagy and the inflammasome.
The majority of age-related macular degeneration (AMD) patients suffer from the geographic atrophy form of the disease (dry AMD), for whom there is no treatment. Dry AMD is featured by retinal pigment epithelial (RPE) cell death and subsequent photoreceptor degeneration. The molecular mechanism(s) underpinning RPE dysfunction in dry AMD remains elusive.However, a recent breakthrough has suggested that activation of the NLRP3 inflammasome and upregulation of IL-18 is a key pathway. Interestingly, IL-18 has also been reported to have an anti-angiogenic role in wet AMD, and it has been suggested that augmenting IL-18 production in dry AMD patients could be a novel therapeutic strategy. In view of these contradictory reports, the role of inflammasome/IL-18 in retinal health under ageing conditions urgently warrants further investigation.
The research team has found that oxidised photoreceptor outer segments can induce NLRP3 inflammasome activation in RPE cells, and that RPE cell autophagy dysfunction can further enhance inflammasome activation. They hypothesise that, with age, RPE cell autophagic activity declines resulting in the accumulation of oxidised proteins/lipids which, in turn, induces inflammasome activation and IL-18 production. Excessive IL-18 production causes RPE cell death and the development of dry AMD.
The project is testing whether NLRP3 inflammasome activation is related to autophagy dysfunction in RPE cells in a mouse model of dry AMD, and whether inflammasome inhibition or IL-18 neutralization can ameliorate retinal lesion. The project will further test whether augmenting RPE autophagy function can prevent or delay retinal lesion development.