Open AccessAdvanced glycation end products‐related modulation of cathepsin L and NF‐κB signalling effectors in retinal pigment epithelium lead to augmented response to TNFα
Author(s) -
Sharif Umar,
Mahmud Nur Musfirah,
Kay Paul,
Yang Yit C.,
Harding Simon P.,
Grierson Ian,
Kamalden Tengku Ain,
Jackson Malcolm J.,
Paraoan Luminita
Publication year - 2019
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13944
Subject(s) - cathepsin b , glycation , retinal pigment epithelium , cathepsin , microbiology and biotechnology , downregulation and upregulation , nf κb , chemistry , cathepsin d , effector , ageing , retinal , senescence , signal transduction , biology , medicine , biochemistry , receptor , enzyme , gene
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 TNF α stimulation, AGE ‐exposed cells had significantly higher ratio of phospho‐p65(Ser536)/total p65 compared to non‐ AGE d 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 TNF α. Thus, NF ‐ κB signalling modulation in the AGE d 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.