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1.
Glia ; 58(16): 1928-36, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20830806

ABSTRACT

Macrophages play an important role in demyelination in multiple sclerosis (MS). Activated macrophages ingest myelin particles, thereby acquiring a foamy appearance. Foamy macrophages in MS lesions were described as being anti-inflammatory. Therefore, these cells might play a role in modulating the inflammatory state of an active lesion. Here, we investigated the mechanism by which myelin uptake leads to skewing of macrophages toward an anti-inflammatory phenotype. Macrophages were incubated with myelin, leading to the development of foamy macrophages. Afterwards, the cells were stimulated with the TLR-4 ligand lipopolysaccharide (LPS), and cytokine production was determined. Interestingly, foamy macrophages appeared to have a reduced cytokine secretion and were LPS insensitive only when generated with one of the myelin preparations. The factor responsible for the different outcomes between different myelin batches turned out to be LPS. We demonstrated that LPS contamination induced insensitivity to LPS in foamy macrophages. On the contrary, foamy macrophages generated in the presence of LPS-free myelin were able to secrete cytokines upon activation. To conclude, myelin-laden macrophages were not LPS insensitive, indicating that they had not acquired an anti-inflammatory phenotype.


Subject(s)
Foam Cells , Interleukin-10/metabolism , Multiple Sclerosis , Myelin Sheath/metabolism , Phagocytosis/immunology , Tumor Necrosis Factor-alpha/metabolism , Cells, Cultured , Foam Cells/immunology , Foam Cells/metabolism , Foam Cells/pathology , Humans , Immunophenotyping , Lipopolysaccharides/pharmacology , Multiple Sclerosis/immunology , Multiple Sclerosis/metabolism , Multiple Sclerosis/pathology , Myelin Sheath/immunology , Toll-Like Receptor 4/metabolism
2.
Glia ; 57(12): 1326-40, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19191324

ABSTRACT

The process of demyelination occurring in diseases as multiple sclerosis is usually investigated in animal models. A major drawback of animal models is that only one condition can be tested per animal, necessitating many animals and systemic effects are factors to be considered. The aim of the study was to develop a reproducible in vitro model for de- and remyelination using whole brain spheroid cultures and lysophosphatidyl choline (LPC). In spheroid cultures, single cell suspensions of embryonic day 15 rodent brain cells reaggregate under constant rotation. Three-dimensional contacts form between the central nervous system cell types present. Multilayered myelin is maximal in four-week old cultures. A week of repeated exposure to LPC led to 30% loss of MBP protein concentration and 2',3'-cyclic nucleotide 3'-phosphodiesterase activity measurements in both rat and mouse spheroids and 56% loss in the number of myelin sheets, with partial remyelination after a week of recovery. The number of dividing cells was increased after LPC exposure and oligodendrocytes were shown to be among the dividing cells. Microglia and astrocytes were not affected and neurons were relatively spared. This suggests that LPC toxicity is specific for myelin and oligodendrocytes. LPC toxicity could be decreased using cholesterol and simvastatin, suggesting that LPC works through altering membrane composition. Thus, in different rodent species and using different read-outs, we could reproducibly show de- and remyelination in spheroid cultures after LPC exposure. This model for demyelination with potential for remyelination offers possibilities for testing novel therapies and studying mechanisms of remyelination.


Subject(s)
Brain/physiology , Demyelinating Diseases , Lysophosphatidylcholines , Models, Neurological , Myelin Sheath/physiology , Spheroids, Cellular/physiology , 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase , Animals , Brain/drug effects , Cell Proliferation/drug effects , Central Nervous System Agents/pharmacology , Cholesterol/pharmacology , Demyelinating Diseases/chemically induced , Demyelinating Diseases/physiopathology , Lysophosphatidylcholines/toxicity , Mice , Mice, Inbred C57BL , Myelin Basic Protein , Nerve Tissue Proteins/metabolism , Neuroglia/drug effects , Neuroglia/physiology , Neurons/drug effects , Neurons/physiology , Phosphoric Diester Hydrolases/metabolism , Rats , Rats, Wistar , Simvastatin/pharmacology , Spheroids, Cellular/drug effects , Time Factors , Transcription Factors/metabolism
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