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The role of macrophages in demyelinating peripheral nervous system of mice heterozygously deficient in p0.

Carenini S, Mäurer M, Werner A, Blazyca H, Toyka KV, Schmid CD, Raivich G, Martini R - J. Cell Biol. (2001)

Bottom Line: This study addresses the functional role of the macrophage in this monogenic myelin disorder.In the P0-deficient double mutants also deficient in M-CSF, the numbers of macrophages were not elevated in the demyelinating motor nerves and demyelination was less severe.These findings demonstrate an active role of macrophages during pathogenesis of inherited demyelination with putative impact on future treatment strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Section of Developmental Neurobiology, University of Würzburg, D-97080 Würzburg, Germany.

ABSTRACT
Mice heterozygously deficient in the p0 gene (P0(+/-)) are animal models for some forms of inherited neuropathies. They display a progressive demyelinating phenotype in motor nerves, accompanied by mild infiltration of lymphocytes and increase in macrophages. We have shown previously that the T lymphocytes are instrumental in the demyelination process. This study addresses the functional role of the macrophage in this monogenic myelin disorder. In motor nerves of P0(+/)- mice, the number of macrophages in demyelinated peripheral nerves was increased by a factor of five when compared with motor nerves of wild-type mice. Immunoelectron microscopy, using a specific marker for mouse macrophages, displayed macrophages not only in the endoneurium of the myelin mutants, but also within endoneurial tubes, suggesting an active role in demyelination. To elucidate the roles of the macrophages, we crossbred the myelin mutants with a spontaneous mouse mutant deficient in macrophage colony-stimulating factor (M-CSF), hence displaying impaired macrophage activation. In the P0-deficient double mutants also deficient in M-CSF, the numbers of macrophages were not elevated in the demyelinating motor nerves and demyelination was less severe. These findings demonstrate an active role of macrophages during pathogenesis of inherited demyelination with putative impact on future treatment strategies.

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Cellular localization of the M-CSF receptor (MCSFR, red) immunoreactivity in teased fiber preparations from ventral roots of P0+/+ and P0+/− mice using antibodies to αMβ2 integrin (green) as a marker for peripheral nerve macrophages. αMβ2-negative cells, such as the adjacent Schwann cells, were never labeled. Note the particularly strongly MCSFR-immunoreactive macrophage in the P0+/− mutant (arrow). Bar, 50 μm.
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Figure 2: Cellular localization of the M-CSF receptor (MCSFR, red) immunoreactivity in teased fiber preparations from ventral roots of P0+/+ and P0+/− mice using antibodies to αMβ2 integrin (green) as a marker for peripheral nerve macrophages. αMβ2-negative cells, such as the adjacent Schwann cells, were never labeled. Note the particularly strongly MCSFR-immunoreactive macrophage in the P0+/− mutant (arrow). Bar, 50 μm.

Mentions: Localization of the M-CSF receptor was performed on teased fibers from ventral roots of 6-mo-old P0+/+ and P0+/− mice by double immunofluorescence using an M-CSF receptor–specific antibody and the macrophage-specific marker αMβ2. Labeling for M-CSF receptor was exclusively associated with macrophages, whereas αMβ2-negative cells, such as Schwann cells and endoneurial fibroblasts, were never labeled with antibodies to M-CSF receptor (Fig. 2). Macrophages of the P0+/+ mice showed a weak labeling for M-CSF receptor (Fig. 2). Interestingly, P0+/− mice showed some very strongly labeled macrophages in addition to weakly labeled macrophages (Fig. 2). These data show that M-CSF receptor expression is confined to macrophages and that expression levels are increased in some macrophages of the P0+/− mice.


The role of macrophages in demyelinating peripheral nervous system of mice heterozygously deficient in p0.

Carenini S, Mäurer M, Werner A, Blazyca H, Toyka KV, Schmid CD, Raivich G, Martini R - J. Cell Biol. (2001)

Cellular localization of the M-CSF receptor (MCSFR, red) immunoreactivity in teased fiber preparations from ventral roots of P0+/+ and P0+/− mice using antibodies to αMβ2 integrin (green) as a marker for peripheral nerve macrophages. αMβ2-negative cells, such as the adjacent Schwann cells, were never labeled. Note the particularly strongly MCSFR-immunoreactive macrophage in the P0+/− mutant (arrow). Bar, 50 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199607&req=5

Figure 2: Cellular localization of the M-CSF receptor (MCSFR, red) immunoreactivity in teased fiber preparations from ventral roots of P0+/+ and P0+/− mice using antibodies to αMβ2 integrin (green) as a marker for peripheral nerve macrophages. αMβ2-negative cells, such as the adjacent Schwann cells, were never labeled. Note the particularly strongly MCSFR-immunoreactive macrophage in the P0+/− mutant (arrow). Bar, 50 μm.
Mentions: Localization of the M-CSF receptor was performed on teased fibers from ventral roots of 6-mo-old P0+/+ and P0+/− mice by double immunofluorescence using an M-CSF receptor–specific antibody and the macrophage-specific marker αMβ2. Labeling for M-CSF receptor was exclusively associated with macrophages, whereas αMβ2-negative cells, such as Schwann cells and endoneurial fibroblasts, were never labeled with antibodies to M-CSF receptor (Fig. 2). Macrophages of the P0+/+ mice showed a weak labeling for M-CSF receptor (Fig. 2). Interestingly, P0+/− mice showed some very strongly labeled macrophages in addition to weakly labeled macrophages (Fig. 2). These data show that M-CSF receptor expression is confined to macrophages and that expression levels are increased in some macrophages of the P0+/− mice.

Bottom Line: This study addresses the functional role of the macrophage in this monogenic myelin disorder.In the P0-deficient double mutants also deficient in M-CSF, the numbers of macrophages were not elevated in the demyelinating motor nerves and demyelination was less severe.These findings demonstrate an active role of macrophages during pathogenesis of inherited demyelination with putative impact on future treatment strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Section of Developmental Neurobiology, University of Würzburg, D-97080 Würzburg, Germany.

ABSTRACT
Mice heterozygously deficient in the p0 gene (P0(+/-)) are animal models for some forms of inherited neuropathies. They display a progressive demyelinating phenotype in motor nerves, accompanied by mild infiltration of lymphocytes and increase in macrophages. We have shown previously that the T lymphocytes are instrumental in the demyelination process. This study addresses the functional role of the macrophage in this monogenic myelin disorder. In motor nerves of P0(+/)- mice, the number of macrophages in demyelinated peripheral nerves was increased by a factor of five when compared with motor nerves of wild-type mice. Immunoelectron microscopy, using a specific marker for mouse macrophages, displayed macrophages not only in the endoneurium of the myelin mutants, but also within endoneurial tubes, suggesting an active role in demyelination. To elucidate the roles of the macrophages, we crossbred the myelin mutants with a spontaneous mouse mutant deficient in macrophage colony-stimulating factor (M-CSF), hence displaying impaired macrophage activation. In the P0-deficient double mutants also deficient in M-CSF, the numbers of macrophages were not elevated in the demyelinating motor nerves and demyelination was less severe. These findings demonstrate an active role of macrophages during pathogenesis of inherited demyelination with putative impact on future treatment strategies.

Show MeSH
Related in: MedlinePlus