The retina is a part of the central nervous system, and as such is subject to a variety of forms of age-related neurodegeneration, culminating in conditions such as macular degeneration. The chronic inflammation characteristic of old age is just as important to neurodegeneration in the retina just as it is in the brain. Inflammatory signaling, necessary and useful in the short term, becomes disruptive to cell and tissue function when sustained over the long term. The causes of chronic inflammation are manifold, a list of much of what goes wrong in cellular biochemistry with age, but most research is focused instead on how this maladaptive inflammatory response is regulated. Development of anti-inflammatory therapies does not focus on removing the cause of inflammatory signaling - which at the end of the day will probably require achieving actual rejuvenation, repair of the cell and tissue damage that causes aging - but instead aims to sabotage the controlling mechanisms of the inflammatory response. This works, but as existing therapies demonstrate, it is hard to sabotage unwanted inflammation without also sabotaging necessary inflammation. Whether there are as yet unexplored approaches that can achieve that goal remains to be seen.
Age-related macular degeneration (AMD) is a fundus oculi disease that progressively impairs the central vision of patients. To date, its pathogenesis has not been fully elucidated, and therapeutic options for dry AMD remain limited. Recently, chronic low-grade inflammation has been recognized as an important pathogenic factor in various neurodegenerative diseases, including AMD. The NLRP3 inflammasome, a key component of the innate immune system, has emerged as a critical integrator of retinal stress signals. This review first delineates the molecular architecture and activation modalities of the NLRP3 inflammasome, encompassing canonical, noncanonical, and alternative pathways, as well as its downstream cell death programs, with a particular focus on pyroptosis and PANoptosis.
We describe how AMD-associated danger signals converge on NLRP3 inflammasome activation within distinct retinal cell populations and discuss how cell-type-specific NLRP3 responses differently shape retinal homeostasis, degeneration, and neovascularization. We further summarize current evidence indicating that the pathological consequences of NLRP3 activation vary across AMD progression, from amplification of chronic inflammation in early and intermediate AMD to promotion of retinal atrophy in geographic atrophy and angiogenic signaling in neovascular AMD. Finally, we evaluate emerging therapeutic strategies targeting the NLRP3 pathway and discuss the major translational challenges related to cell-type and disease-stage specificity, retinal delivery, and long-term safety.
senescence-associated inflammation, inflammatory cell death, disease phenotypes, and therapeutic opportunities into a unified framework, this review provides a comprehensive perspective on the role of NLRP3 inflammasome signaling in AMD pathogenesis and treatment.
Link: https://doi.org/10.3389/fnagi.2026.1817987
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