Studies link drusen deposits with NLRP3 inflammasome activation and IL-18 production.
Increasing levels of interleukin 18 (IL-18) in the eye could help protect against the development and progression of age-related macular degeneration (AMD), scientists claim. Researchers at Trinity College Dublin and colleagues have shown that extracellular protein deposits known as Drusen, which characteristically accumulate in the macula during the early stages of AMD, activate the NLRP3 inflammasome, causing secretion of interleukin-1β (IL-1β) and IL-18.
Their studies in mouse models then directly implicated IL-18 in the regulation of laser-induced choroidal neovascularisation (CNV) development, a mouse model of the more advanced, eventually blinding “wet” form of AMD, and indicated a protective role for NLRP3 and IL-18 in progression of the disease. This notion was supported further by the finding that mice deficient in NLRP3 more readily developed CNV. The investigators separately identified activated caspase-1 and NLRP3 in macrophages surrounding drusen-like lesions in the retinas mice immunized with CEP-adducted mouse serum albumin (CEP-MSA), which is a model of the earlier, “dry” form of AMD that can progress to wet AMD. Caspase-1 is the cysteine protease that is activated in the inflammasome complex to cleave pro–IL-1β and pro–IL-18 into their mature forms.
Reporting in Nature Medicine, Trinity’s Matthew Campbell, M.D., Sarah Doyle, M.D., and colleagues say their findings indicate that boosting levels of IL-18 in the retina could represent a new therapeutic strategy for AMD, and prevent patients with dry AMD from progressing to the wet form of the disease. The published paper is titled “NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components.”
In essence, the reported studies indicate that a small amount of Drusen accumulation isn’t necessarily detrimental because the IL-18 production induced prevents the abnormal growth of blood vessels characteristic of the wet form of AMD. However, once a threshold level of drusen accumulation is reached, the scales are tipped in favor of disease progression, the team writes.
“Activation of the NLRP3 inflammasome by drusen suggests that a balance may exist whereby a certain focal amount of drusen is tolerated because of its ability to induce IL-18, which, in turn, may act as an anti-angiogenic effector, maintaining choroidal homeostasis in an inflammatory microenvironment,” the authors conclude. “It is probable that once a critical level of drusen accumulates, its protective role is negated by the excessive damage to the surrounding tissues that it causes. Notably, we have shown that drusen-inducible inflammatory mediators are protective against CNV development and that it is the resultant NLRP3-mediated elevation of IL-18 concentrations that prevents the downstream production of VEGF.”