Age-related macular degeneration (AMD) is a complex and progressive degenerative eye disease resulting in severe loss of central vision. Recent evidence indicates that immune system dysregulation could contribute to the development of AMD. We hypothesize that defective lysosome-mediated clearance causes accumulation of waste products in the retinal pigmented epithelium (RPE), activating the immune system and leading to retinal tissue injury and AMD. We have generated unique genetically engineered mice in which lysosome-mediated clearance (both by phagocytosis and autophagy) in RPE cells is compromised, causing the development of features of early AMD. Our recent data indicate a link between lipocalin-2 (LCN-2) and the inflammatory responses induced in this mouse model. We show that nuclear factor-κB (NF-κB) and STAT-1 may function as a complex in our animal model system, together controlling the upregulation of LCN-2 expression in the retina and stimulating an inflammatory response. This study revealed increased infiltration of LCN-2-positive neutrophils in the choroid and retina of early AMD patients as compared with age-matched controls. Our results demonstrate that, both in our animal model and in human AMD, the AKT2–NF-κB–LCN-2 signalling axis is involved in activating the inflammatory response, making this pathway a potential target for AMD treatment.
Bibliographical noteFunding Information:
We thank Drs Morton Goldberg and Eric Wawrousek for critical reading and discussions regarding this manuscript, and the personnel at the Minnesota Lions Eye Bank for assistance with procuring and processing donor eyes. We thank Drs Mariko Bennett and Ben Barres for the Tmem119 antibody. SG is a recipient of a Fulbright-Nehru Doctoral Research Fellowship. DS is a recipient of the Carolyn K. McGillvray Memorial Award for Macular Degeneration Research from BrightFocus Foundation and the Sybil B. Harrington Special Scholar Award for Macular Degeneration from Research to Prevent Blindness. This research was supported by BrightFocus Foundation (DS), Research to Prevent Blindness (an unrestricted grant to the Wilmer Eye Institute and Department of Ophthalmology and Visual Sciences, University of Minnesota), National Eye Institute EY019037-S (DS) and EY01765 (Wilmer Imaging Core), the Arnold and Mabel and Beckman Foundation (DF), and an anonymous benefactor for AMD research (DF).
- AKT2–NF-κB–lipocalin-2 signalling axis
- age-related macular degeneration