title: Activating the AKT2-nuclear factor-κB-lipocalin-2 axis elicits an inflammatory response in age-related macular degeneration.
abstract: 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. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Physiology, University of Calcutta, Kolkata, WB, India.
authors.forename: Sayan
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Shang
authors.affiliation: Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Meysam
authors.initials: M
authors.lastname: Yazdankhah
authors.affiliation: Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Imran
authors.initials: I
authors.lastname: Bhutto
authors.affiliation: Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Hose
authors.affiliation: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Montezuma
authors.affiliation: Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Tianqi
authors.initials: T
authors.lastname: Luo
authors.affiliation: Department of Physiology, University of Calcutta, Kolkata, WB, India.
authors.forename: Sreya
authors.initials: S
authors.lastname: Chattopadhyay
authors.affiliation: Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Qian
authors.affiliation: Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Lutty
authors.affiliation: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Ferrington
authors.affiliation: Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: J Samuel
authors.initials: JS
authors.lastname: Zigler
authors.affiliation: Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Debasish
authors.initials: D
authors.lastname: Sinha
mesh_terms: D000367:Age Factors; D000818:Animals; D001343:Autophagy; D002829:Choroid / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation; D000071068:Lipocalin-2 / Q000235:genetics* / Q000378:metabolism; D008247:Lysosomes / Q000276:immunology* / Q000378:metabolism; D008268:Macular Degeneration / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D010587:Phagocytosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D012160:Retina / Q000276:immunology / Q000293:injuries / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: C489506:LCN2 protein, human; D000071068:Lipocalin-2; D016328:NF-kappa B; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT2-NF-κB-lipocalin-2 signalling axis; age-related macular degeneration; inflammation; lysosomes; βA3/A1-crystallin