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Degradation of superparamagnetic iron oxide nanoparticle-induced ferritin by lysosomal cathepsins and related immune response
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
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2012 (English)In: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 7, no 5, 705-717 p.Article in journal (Refereed) Published
Abstract [en]

Aim: To examine the physiological impact of superparamagnetic iron oxide nanoparticles (SPIONs) on cell function and its interaction with oxysterol laden cells. Materials andamp; methods: Intracellular iron was determined by Prussian blue staining. Cellular ferritin, cathepsin L and ferroportin were analyzed by flow cytometry and fluorescence microscopy. Cytokine secretion was determined by ELISA and immunoblotting. Results: In U937 and THP 1 cells, we did not detect any loss of cell viability on SPION loading. Desferrioxamine prevents induction of both ferritin and cathepsin L by SPIONs. Inhibition of lysosomal cathepsins upregulates both endogenous- and SPION-induced ferritin. SPION loading induces membranous ferroportin and incites secretion of ferritin, TNF-alpha and IL-10. 7 beta-hydroxycholesterol exposure reduces SPION uptake by cells. Conclusion: SPION loading results in upregulation of lysosomal cathepsin, membranous ferroportin and ferritin degradation, which is associated with secretion of both pro- and anti-inflammatory cytokines. A reduced SPION uptake by oxysterol-laden cells may lead to a compromised MRI with elevated cathepsins and ferritin.

Place, publisher, year, edition, pages
Future Medicine , 2012. Vol. 7, no 5, 705-717 p.
Keyword [en]
atherosclerosis, cytokine, degradation, iron, lysosomal, monocyte, nanoparticle
National Category
Engineering and Technology
URN: urn:nbn:se:liu:diva-78580DOI: 10.2217/nnm.11.148ISI: 000304238300016OAI: diva2:534155

Funding Agencies|Swedish Heart Lung Foundation||research fund of Torsten och Ragnar Soderbergs||research fund of Stroke||research fund of Gamla Tjanarinnor||Linkoping University Hospital||

Available from: 2012-06-15 Created: 2012-06-15 Last updated: 2014-10-30
In thesis
1. Cell response to imaging contrast agents suggested for atherosclerotic plaque imaging
Open this publication in new window or tab >>Cell response to imaging contrast agents suggested for atherosclerotic plaque imaging
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Oxysterols are the major cytotoxic components of oxidized low-density lipoprotein (OxLDL) that accumulate in atherosclerotic plaques. Their uptake by macrophages ensue foam cell formation, atherogenesis and plaque progression. Magnetic resonance imaging (MRI) has grown as a modality to track such intra-plaque developments by using intracellular contrast agents. The focus of this study was to evaluate the effects of two contrast agents; manganese based mangafodipir (TeslascanTM) and iron based super-paramagnetic iron oxide nanoparticles (SPION, ResovistTM) on cell functions and examined their interaction with oxysterol laden cells.

Mangafodipir has antioxidant property and provides protection against oxidative stress. The chemical structure of mangafodipir comprises of organic ligand fodipir (Dipyridoxyl diphosphate, Dp-dp) and Mn (manganese). Mangafodipir is readily metabolized within the body to manganese dipyridoxyl ethyldiamine (MnPLED) after an intravenous injection. MnPLED has superoxide dismutase (SOD) mimetic activity, and Dp-dp has iron chelating effects. The second contrast agent tested in this study is ResovistTM. These SPION are primarily ingested by macrophages and accumulated in lysosomes where they are gradually degraded ensuing increased cellular iron.

In paper I, we examined whether the above-noted effects of mangafodipir could be utilized to prevent 7β-hydroxycholesterol (7βOH) induced cell death. We found that mangafodipir prevents 7βOH induced cell death by attenuating reactive oxygen species (ROS) and by preserving lysosomal membrane integrity and mitochondrial membrane potential.

The second part of this study (paper II) was designed to identify the pharmacologically active part of mangafodipir, which exerts the above-noted effects. We compared the activity of parent compound (mangafodipir) with MnPLED and Dp-dp. We found that mangafodipir; MnPLED and Dp-dp provide similar cyto-protection against 7βOH induced cell death. These results suggest that MnPLED and Dp-dp both contribute to the pharmacologically active part of mangafodipir.

In paper III, we aimed to examine the interaction of SPION with monocytes and macrophages exposed or not to atheroma relevant oxysterols. We demonstrate that SPION loading up-regulates cellular levels of cathepsin and ferritin and induces membranous ferroportin expression. Additionally, SPION incites secretion of ferritin and both pro-inflammatory and anti-inflammatory cytokines. Moreover, exposure to oxysterols resulted in a reduced SPION uptake by cells, which may lead to inefficient targeting of such cells. Although SPION uptake was reduced, the ingested amounts significantly up-regulated the expression of 7βOH induced cathepsin B, cathepsin L and ferritin in cells, which may further aggravate atherogenesis.

The fourth part of the study (paper IV) was designed to examine the interaction of SPION with macrophage subtypes and compare the cellular effects of coated and uncoated iron-oxide nanoparticles. We found that iron in SPION induces a phenotypic shift in THP1 M2 macrophages towards a macrophage subtype characterized by upregulated intracellular levels of CD86, ferritin and cathepsin L. Differential levels of these proteins among macrophage subtypes might be important to sustain a functional plasticity. Additionally, uncoated iron-oxide nanoparticles induced dose dependent cell death in macrophages, which elucidates the potential cyto-toxicity of iron in iron-oxide nanoparticles.

In conclusion, evidence is provided in this study that intracellular MRI contrast agents have the potential to modulate cell functions. The study reveals a therapeutic potential of mangafodipir, which could be utilized for future development of contrast agents with both diagnostic and curative potentials. Additionally, we found that surface coating in SPION may provide cell tolerance to iron toxicity by modulation of cellular iron metabolism and cell functions. Such alterations in cellular metabolism call for careful monitoring and also highlight new concepts for development of iron containing nanoparticles. A reduced uptake of SPION by atheroma relevant cells justifies development of functionalized SPION to target such cells in atherosclerotic plaques.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. 73 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1357
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-92003 (URN)978-91-7519-671-8 (print) (ISBN)
Public defence
2013-05-31, Nils Holger, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Available from: 2013-05-07 Created: 2013-05-07 Last updated: 2013-05-07Bibliographically approved

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