Project: C07

NLRP3 inflammasome as therapeutic target in atrophic age-related macular degeneration

Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in developed countries, and effective treatment options for the blinding atrophic late stage of the disease are lacking. Hence, there is a high unmet medical need for new therapies for atrophic AMD. Accumulating oxidative/photooxidative damage to the retinal pigment epithelium (RPE), progressive deposition of lipofuscin within the RPE, and chronic local activation of the innate immune system in the outer retina are all factors that are demonstrated to be crucially involved in AMD development and progression. A central regulator of the innate immune system is the intracellular protein complex called ‘the inflammasome’. Inflammasomes act as intracellular sensors for a variety of cellular danger signals and controls the cellular release of highly inflammatory cytokines such as IL-1β and IL-18. Activation of the NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome has been demonstrated in the RPE and retina of patients with atrophic AMD.

We have investigated the mechanisms of interactions between the above-mentioned factors of AMD pathogenesis. We have identified lipofuscin-mediated photooxidative damage to lysosomal membranes as a trigger of NLRP3 inflammasome activation in the RPE that may contribute to AMD. We also demonstrated cross-talk of the NLRP3 signaling pathway in the RPE with retinal microglia and the complement system, and we characterized the mechanisms of RPE cell death in response to NLRP3 inflammasome activation.

In this project, we aim to further elucidate the role of inflammasome activation in atrophic AMD and to develop immunomodulatory treatment strategies. For this, we will investigate NRLP3 inflammasome activation triggered by lipofuscin-mediated photooxidative damage to the RPE, using novel in vivo mouse and ex vivo retinal tissue culture models of AMD. We seek to identify the molecular mechanisms and retinal cell types affected and to test the efficacy of selective NLRP3 inhibitory compounds in suppressing these processes in the retina, thus providing the groundwork for the development of inflammasome inhibitors as a potential treatment for atrophic AMD.