Activating the AKT2-nuclear factor-κB-lipocalin-2 axis elicits an inflammatory response in age-related macular degeneration

Sayan Ghosh, Peng Shang, Meysam Yazdankhah, Imran Bhutto, Stacey Hose, Sandra R. Montezuma, Tianqi Luo, Sreya Chattopadhyay, Jiang Qian, Gerard Anthony Lutty, Deborah A. Ferrington, J. Samuel Zigler, Debasish Sinha

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalJournal of Pathology
DOIs
StateAccepted/In press - 2017

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Macular Degeneration
Lysosomes
Retina
Immune System
Epithelium
Animal Models
Waste Products
Choroid
Eye Diseases
Autophagy
Lipocalin-2
Phagocytosis
Neutrophils
Up-Regulation
Wounds and Injuries

Keywords

  • Age-related macular degeneration
  • AKT2-NF-κB-lipocalin-2 signalling axis
  • Inflammation
  • Lysosomes
  • βA3/A1-crystallin

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Activating the AKT2-nuclear factor-κB-lipocalin-2 axis elicits an inflammatory response in age-related macular degeneration. / Ghosh, Sayan; Shang, Peng; Yazdankhah, Meysam; Bhutto, Imran; Hose, Stacey; Montezuma, Sandra R.; Luo, Tianqi; Chattopadhyay, Sreya; Qian, Jiang; Lutty, Gerard Anthony; Ferrington, Deborah A.; Zigler, J. Samuel; Sinha, Debasish.

In: Journal of Pathology, 2017.

Research output: Contribution to journalArticle

Ghosh, Sayan ; Shang, Peng ; Yazdankhah, Meysam ; Bhutto, Imran ; Hose, Stacey ; Montezuma, Sandra R. ; Luo, Tianqi ; Chattopadhyay, Sreya ; Qian, Jiang ; Lutty, Gerard Anthony ; Ferrington, Deborah A. ; Zigler, J. Samuel ; Sinha, Debasish. / Activating the AKT2-nuclear factor-κB-lipocalin-2 axis elicits an inflammatory response in age-related macular degeneration. In: Journal of Pathology. 2017.
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