Advanced glycation end products-related modulation of cathepsin L and NF-κB signalling effectors in retinal pigment epithelium lead to augmented response to TNFα

Umar Sharif, Nur Musfirah Mahmud, Paul Kay, Yit C Yang, Simon P Harding, Ian Grierson, Tengku Ain Kamalden, Malcolm J Jackson, Luminita Paraoan

Research output: Contribution to journalArticle (journal)peer-review

10 Citations (Scopus)

Abstract

The retinal pigment epithelium (RPE) plays a central role in neuroretinal homoeostasis throughout life. Altered proteolysis and inflammatory processes involving RPE contribute to the pathophysiology of age-related macular degeneration (AMD), but the link between these remains elusive. We report for the first time the effect of advanced glycation end products (AGE)-known to accumulate on the ageing RPE's underlying Bruch's membrane in situ-on both key lysosomal cathepsins and NF-κB signalling in RPE. Cathepsin L activity and NF-κB effector levels decreased significantly following 2-week AGE exposure. Chemical cathepsin L inhibition also decreased total p65 protein levels, indicating that AGE-related change of NF-κB effectors in RPE cells may be modulated by cathepsin L. However, upon TNFα stimulation, AGE-exposed cells had significantly higher ratio of phospho-p65(Ser536)/total p65 compared to non-AGEd controls, with an even higher fold increase than in the presence of cathepsin L inhibition alone. Increased proportion of active p65 indicates an AGE-related activation of NF-κB signalling in a higher proportion of cells and/or an enhanced response to TNFα. Thus, NF-κB signalling modulation in the AGEd environment, partially regulated via cathepsin L, is employed by RPE cells as a protective (para-inflammatory) mechanism but renders them more responsive to pro-inflammatory stimuli.

Original languageEnglish
Pages (from-to)405-416
Number of pages12
JournalJournal of Cellular and Molecular Medicine
Volume23
Issue number1
DOIs
Publication statusPublished - 19 Oct 2019
Externally publishedYes

Keywords

  • Cathepsin L/metabolism
  • Cells, Cultured
  • Glycation End Products, Advanced/metabolism
  • Humans
  • Macular Degeneration/metabolism
  • NF-kappa B/metabolism
  • Retinal Pigment Epithelium/metabolism
  • Signal Transduction/physiology
  • Tumor Necrosis Factor-alpha/metabolism

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