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Lysosomal oxidation of LDL alters lysosomal pH, induces senescence and increases secretion of pro-inflammatory cytokines in human macrophages

Ahmad, F. and Leake, D. S. (2019) Lysosomal oxidation of LDL alters lysosomal pH, induces senescence and increases secretion of pro-inflammatory cytokines in human macrophages. Journal of Lipid Research, 60. pp. 98-110. ISSN 1539-7262

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To link to this item DOI: 10.1194/jlr.M088245

Abstract/Summary

Objective We have shown that aggregated low density lipoproteins (LDL) is internalised by macrophages and oxidised in lysosomes by redox-active iron. We have now investigated if the lysosomal oxidation of LDL impairs lysosomal function and if a lysosomotropic antioxidant can prevent these alterations. Approach and Results LDL aggregated by sphingomyelinase (SMase-LDL) caused increased lysosomal lipid peroxidation in human monocyte-derived macrophages or THP-1 macrophage-like cells, as shown by a fluorescent probe, Foam-LPO. The pH of the lysosomes was increased considerably by lysosomal LDL oxidation as shown by Lysosensor Yellow/Blue and LysoTracker Red. SMase-LDL induced senescence-like properties in the cells as shown by β-galactosidase staining and levels of p53 and p21. Inflammation plays a key role in atherosclerosis. SMase-LDL treatment increased the LPS-induced secretion of TNF-α, IL-6 and MCP-1. The lysosomotropic antioxidant, cysteamine inhibited all of the above changes. Conclusions Targeting lysosomes with antioxidants, such as cysteamine, to prevent the intralysosomal oxidation of LDL might be a novel therapy for atherosclerosis.

Item Type:Article
Refereed:Yes
Divisions:Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR)
Faculty of Life Sciences > School of Biological Sciences > Biomedical Sciences
ID Code:80740
Publisher:American Society for Biochemistry and Molecular Biology

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