Investigating the production and function of Lipocalin-2 in retinal pigment epithelial cells in retinal health and disease

  • Orlaith O'Shaughnessy

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

RPE dysregulation is known to be involved in age-related macular degeneration (AMD) which is the leading cause of vision loss in the elderly of developed nations. There are two types of AMD which are known as neovascular AMD (nAMD) and geographic atrophy (GA). nAMD patients maybe treated with anti-VEGF intravitreal injections however, 20–40% of nAMD patients do not adequately or fully respond to anti-VEGF treatment. Therefore, new treatment options are urgently required.  

Levels of the acute stress response protein, lipocalin-2 (LCN2), were significantly increased in the blood plasma of nAMD patients with secondary fibrosis compared to healthy controls. Immunohistochemical studies demonstrated that LCN2 is upregulated in the murine RPE but concluded that LCN2 does not appear to have a role to play in fibrosis. LCN2 production by RPE cells was almost undetectable under normal conditions but LCN2 levels were significantly upregulated in response to the proinflammatory conditions induced by the TLR1/2 ligandPam3CSK4, the TLR4 ligand LPS, and the TLR6/2 ligand FSL-1. However, the ligands of the other tested TLRs did not have any significant effect on LCN2 production. IL-1α, IL-1β, and IL-33 all significantly upregulated LCN2 production from B6-RPE07 but IL-18 had no effect. LCN2expression was upregulated in the RPE and retina in mice with EAU in comparison to wild type(WT) mice.  

Recombinant LCN2 (rmLCN2) did not play a role in wound healing of B6-RPE07 cells nor didrmLCN2 promote epithelial-mesenchymal transition (EMT) in primary RPE cells. However,rmLCN2 did significantly reduce IL-33 gene expression in primary RPE cells and rmLCN2 rescuedB6-RPE07 cells from oxidative stress. These results suggest LCN2 may have an anti-inflammatory role to play within the RPE. Future studies to understand LCN2’s function in the RPE under inflammatory conditions may help with the development of more effective AMD treatment strategies.

Thesis embargoed until 31st July 2028
Date of AwardJul 2023
Original languageEnglish
Awarding Institution
  • Queen's University Belfast
SponsorsNorthern Ireland Department for the Economy
SupervisorHeping Xu (Supervisor), Mei Chen (Supervisor) & Tim Curtis (Supervisor)

Keywords

  • LCN2
  • NGAL
  • Lipocalin-2
  • AMD
  • retinal pigment epithelium
  • disease
  • RPE
  • TLR
  • Inflammation
  • eye
  • immunology
  • EMT
  • Age-related macular degeneration
  • Ocular
  • B6-RPE07

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