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Altered proteolysis and inflammatory processes involving <jats:styled-content style=\"fixed-case\">RPE<\/jats:styled-content> contribute to the pathophysiology of age\u2010related macular degeneration (<jats:styled-content style=\"fixed-case\">AMD<\/jats:styled-content>), but the link between these remains elusive. We report for the first time the effect of advanced glycation end products (<jats:styled-content style=\"fixed-case\">AGE<\/jats:styled-content>)\u2014known to accumulate on the ageing <jats:styled-content style=\"fixed-case\">RPE<\/jats:styled-content>'s underlying Bruch's membrane in\u00a0situ\u2014on both key lysosomal cathepsins and <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">\u03baB<\/jats:styled-content> signalling in <jats:styled-content style=\"fixed-case\">RPE<\/jats:styled-content>. Cathepsin L activity and <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">\u03baB<\/jats:styled-content> effector levels decreased significantly following 2\u2010week <jats:styled-content style=\"fixed-case\">AGE<\/jats:styled-content> exposure. Chemical cathepsin L inhibition also decreased total p65 protein levels, indicating that <jats:styled-content style=\"fixed-case\">AGE<\/jats:styled-content>\u2010related change of <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">\u03baB<\/jats:styled-content> effectors in <jats:styled-content style=\"fixed-case\">RPE<\/jats:styled-content> cells may be modulated by cathepsin L. However, upon <jats:styled-content style=\"fixed-case\">TNF<\/jats:styled-content>\u03b1 stimulation, <jats:styled-content style=\"fixed-case\">AGE<\/jats:styled-content>\u2010exposed cells had significantly higher ratio of phospho\u2010p65(Ser536)\/total p65 compared to non\u2010<jats:styled-content style=\"fixed-case\">AGE<\/jats:styled-content>d controls, with an even higher fold increase than in the presence of cathepsin L inhibition alone. Increased proportion of active p65 indicates an <jats:styled-content style=\"fixed-case\">AGE<\/jats:styled-content>\u2010related activation of <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">\u03baB<\/jats:styled-content> signalling in a higher proportion of cells and\/or an enhanced response to <jats:styled-content style=\"fixed-case\">TNF<\/jats:styled-content>\u03b1. Thus, <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">\u03baB<\/jats:styled-content> signalling modulation in the <jats:styled-content style=\"fixed-case\">AGE<\/jats:styled-content>d environment, partially regulated via cathepsin L, is employed by <jats:styled-content style=\"fixed-case\">RPE<\/jats:styled-content> cells as a protective (para\u2010inflammatory) mechanism but renders them more responsive to pro\u2010inflammatory stimuli.<\/jats:p>","DOI":"10.1111\/jcmm.13944","type":"journal-article","created":{"date-parts":[[2018,10,19]],"date-time":"2018-10-19T09:29:38Z","timestamp":1539941378000},"page":"405-416","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Advanced glycation end products\u2010related modulation of cathepsin L and NF\u2010\u03baB signalling effectors in retinal pigment epithelium lead to augmented response to 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