On the cytoprotective role of ferritin in macrophages and its ability to enhance lysosomal stability.
Macrophages have a great capacity to take up (e.g. by endocytosis and phagocytosis) exogenous sources of iron which could potentially become cytotoxic, particularly following the intralysosomal formation of low-molecular weight, redox active iron, and under conditions of oxidative stress. Following autophagocytosis of endogenous ferritin/apoferritin, these compounds may serve as chelators of such lysosomal iron and counteract the occurrence of iron-mediated intralysosomal oxidative reactions. Such redox-reactions have been shown to lead to destabilisation of lysosomal membranes and result in leakage of damaging lysosomal contents to the cytosol. In this study we have shown: (i) human monocyte-derived macrophages to accumulate ferritin in response to iron exposure; (ii) iron to destabilise macrophage secondary lysosomes when the cells are exposed to H2O2; and (iii) endocytosed apoferritin to act as a stabiliser of the acidic vacuolar compartment of iron-loaded macrophages. While the endogenous ferritin accumulation which was induced by iron exposure was not sufficient to protect cells from the damaging effects of H2O2, exogenously added apoferritin, as well as the potent iron chelator desferrioxamine, afforded significant protection. It is suggested that intralysosomal formation of haemosiderin, from partially degraded ferritin, is a protective strategy to suppress intralysosomal iron-catalysed redox reactions. However, under conditions of severe macrophage lysosomal iron-overload, induction of ferritin synthesis is not enough to completely prevent the enhanced cytotoxic effects of H2O2.
Garner
B
B
Department of Biomedical Science, University of Wollongong, NSW, Australia. brett_garner@uow.edu.au
Li
W
W
Roberg
K
K
Brunk
U T
UT
D000818:Animals; D001052:Apoferritins / Q000494:pharmacology; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D005293:Ferritins / Q000032:analysis / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007425:Intracellular Membranes / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D005293:Ferritins; D001052:Apoferritins; D006861:Hydrogen Peroxide; D003676:Deferoxamine