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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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(A and B) Electron microscopy of ventral roots of 6-mo-old P0+/− op/wt (A) and P0+/− op/op mice (B). Myelin thickness in P0+/− op/wt mice is profoundly reduced compared with P0+/− op/op littermates. Note that in P0+/− op/wt mice (A) both small (asterisk) and large caliber fibers (double asterisk) are associated with abnormally thin myelin. The presence of fibers with thicker and thinner myelin in one and the same section in A represents segmental demyelination as has been described previously in longitudinal views of teased fibers (Martini et al. 1995). (C) Quantitative analysis of g-ratios of myelinated fibers in ventral roots of P0+/− op/wt (dark gray bars, n = 3), P0+/− op/op (bright gray bars, n = 3), and P0+/+ mice (black bars, n = 3) at the age of six months. Note the reduction in g-ratios in roots from P0+/− op/op mice reflecting thicker myelin sheaths, when compared with values from P0+/− op/wt mice. *P < 0.05. P0+/+ mice display the thickest myelin sheaths. Bars, 5 μm.
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Figure 5: (A and B) Electron microscopy of ventral roots of 6-mo-old P0+/− op/wt (A) and P0+/− op/op mice (B). Myelin thickness in P0+/− op/wt mice is profoundly reduced compared with P0+/− op/op littermates. Note that in P0+/− op/wt mice (A) both small (asterisk) and large caliber fibers (double asterisk) are associated with abnormally thin myelin. The presence of fibers with thicker and thinner myelin in one and the same section in A represents segmental demyelination as has been described previously in longitudinal views of teased fibers (Martini et al. 1995). (C) Quantitative analysis of g-ratios of myelinated fibers in ventral roots of P0+/− op/wt (dark gray bars, n = 3), P0+/− op/op (bright gray bars, n = 3), and P0+/+ mice (black bars, n = 3) at the age of six months. Note the reduction in g-ratios in roots from P0+/− op/op mice reflecting thicker myelin sheaths, when compared with values from P0+/− op/wt mice. *P < 0.05. P0+/+ mice display the thickest myelin sheaths. Bars, 5 μm.

Mentions: The thickness of myelin was a particularly striking parameter in the presence or absence of M-CSF. Motor nerves from P0+/− op/op mice always had thicker myelin sheaths than those from the P0+/− op/wt littermates. This difference was strongest in the ventral roots (Fig. 5A and Fig. B), but substantial differences in myelin thickness between P0+/− op/wt and P0+/− op/op mice were also obtained for the quadriceps nerves (not shown). Semithin sections of quadriceps nerves and ventral roots of P0+/+ op/wt and P0+/+ op/op mice were also investigated at the age of 6 mo. These nerves were of normal phenotype with thick myelin and absence of features indicative of demyelination independent of the op genotype (not shown).


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)

(A and B) Electron microscopy of ventral roots of 6-mo-old P0+/− op/wt (A) and P0+/− op/op mice (B). Myelin thickness in P0+/− op/wt mice is profoundly reduced compared with P0+/− op/op littermates. Note that in P0+/− op/wt mice (A) both small (asterisk) and large caliber fibers (double asterisk) are associated with abnormally thin myelin. The presence of fibers with thicker and thinner myelin in one and the same section in A represents segmental demyelination as has been described previously in longitudinal views of teased fibers (Martini et al. 1995). (C) Quantitative analysis of g-ratios of myelinated fibers in ventral roots of P0+/− op/wt (dark gray bars, n = 3), P0+/− op/op (bright gray bars, n = 3), and P0+/+ mice (black bars, n = 3) at the age of six months. Note the reduction in g-ratios in roots from P0+/− op/op mice reflecting thicker myelin sheaths, when compared with values from P0+/− op/wt mice. *P < 0.05. P0+/+ mice display the thickest myelin sheaths. Bars, 5 μm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2199607&req=5

Figure 5: (A and B) Electron microscopy of ventral roots of 6-mo-old P0+/− op/wt (A) and P0+/− op/op mice (B). Myelin thickness in P0+/− op/wt mice is profoundly reduced compared with P0+/− op/op littermates. Note that in P0+/− op/wt mice (A) both small (asterisk) and large caliber fibers (double asterisk) are associated with abnormally thin myelin. The presence of fibers with thicker and thinner myelin in one and the same section in A represents segmental demyelination as has been described previously in longitudinal views of teased fibers (Martini et al. 1995). (C) Quantitative analysis of g-ratios of myelinated fibers in ventral roots of P0+/− op/wt (dark gray bars, n = 3), P0+/− op/op (bright gray bars, n = 3), and P0+/+ mice (black bars, n = 3) at the age of six months. Note the reduction in g-ratios in roots from P0+/− op/op mice reflecting thicker myelin sheaths, when compared with values from P0+/− op/wt mice. *P < 0.05. P0+/+ mice display the thickest myelin sheaths. Bars, 5 μm.
Mentions: The thickness of myelin was a particularly striking parameter in the presence or absence of M-CSF. Motor nerves from P0+/− op/op mice always had thicker myelin sheaths than those from the P0+/− op/wt littermates. This difference was strongest in the ventral roots (Fig. 5A and Fig. B), but substantial differences in myelin thickness between P0+/− op/wt and P0+/− op/op mice were also obtained for the quadriceps nerves (not shown). Semithin sections of quadriceps nerves and ventral roots of P0+/+ op/wt and P0+/+ op/op mice were also investigated at the age of 6 mo. These nerves were of normal phenotype with thick myelin and absence of features indicative of demyelination independent of the op genotype (not shown).

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