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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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Quantification of F4/80-positive macrophages in quadriceps and saphenous nerves of P0+/+ op/wt (black bars, n = 5), P0+/+ op/op (white bars, n = 3), P0+/− op/wt (dark gray bars, n = 9), and P0+/− op/op mice (bright gray bars, n = 3) at the age of 6 mo. The op genotype has no influence on the number of resident macrophages in quadriceps nerves of P0+/+ mice. In quadriceps nerves of P0+/− op/wt mice, the number of macrophages is similarly increased, as shown in Fig. 1 C, whereas homozygosity for op prevents the increase of macrophage numbers in quadriceps nerves of the myelin mutants (P0+/− op/op). In the nondemyelinating saphenous nerves, the number of macrophages is never increased. Bars indicate mean values ± SD. *P < 0.05.
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Figure 4: Quantification of F4/80-positive macrophages in quadriceps and saphenous nerves of P0+/+ op/wt (black bars, n = 5), P0+/+ op/op (white bars, n = 3), P0+/− op/wt (dark gray bars, n = 9), and P0+/− op/op mice (bright gray bars, n = 3) at the age of 6 mo. The op genotype has no influence on the number of resident macrophages in quadriceps nerves of P0+/+ mice. In quadriceps nerves of P0+/− op/wt mice, the number of macrophages is similarly increased, as shown in Fig. 1 C, whereas homozygosity for op prevents the increase of macrophage numbers in quadriceps nerves of the myelin mutants (P0+/− op/op). In the nondemyelinating saphenous nerves, the number of macrophages is never increased. Bars indicate mean values ± SD. *P < 0.05.

Mentions: In the quadriceps nerve of M-CSF–deficient, P0 heterozygous mice (P0+/− op/op), the number of macrophages was not increased compared with mice with normal P0 dosage (P0+/+ op/wt and P0+/+ op/op; Fig. 4). In contrast, and similar to the findings obtained from P0+/− mice (Fig. 1 C), the number of macrophages in the quadriceps nerve was strongly elevated in P0+/− op/wt mice compared with op mutants with normal P0 gene dosage (P0+/+ op/wt and P0+/+ op/op mice; P = 0.01; Fig. 4). Thus, homozygous deficiency in M-CSF leads to a lack of an age-dependent macrophage increase in the motor nerves of P0+/− mutants.


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)

Quantification of F4/80-positive macrophages in quadriceps and saphenous nerves of P0+/+ op/wt (black bars, n = 5), P0+/+ op/op (white bars, n = 3), P0+/− op/wt (dark gray bars, n = 9), and P0+/− op/op mice (bright gray bars, n = 3) at the age of 6 mo. The op genotype has no influence on the number of resident macrophages in quadriceps nerves of P0+/+ mice. In quadriceps nerves of P0+/− op/wt mice, the number of macrophages is similarly increased, as shown in Fig. 1 C, whereas homozygosity for op prevents the increase of macrophage numbers in quadriceps nerves of the myelin mutants (P0+/− op/op). In the nondemyelinating saphenous nerves, the number of macrophages is never increased. Bars indicate mean values ± SD. *P < 0.05.
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Related In: Results  -  Collection

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Figure 4: Quantification of F4/80-positive macrophages in quadriceps and saphenous nerves of P0+/+ op/wt (black bars, n = 5), P0+/+ op/op (white bars, n = 3), P0+/− op/wt (dark gray bars, n = 9), and P0+/− op/op mice (bright gray bars, n = 3) at the age of 6 mo. The op genotype has no influence on the number of resident macrophages in quadriceps nerves of P0+/+ mice. In quadriceps nerves of P0+/− op/wt mice, the number of macrophages is similarly increased, as shown in Fig. 1 C, whereas homozygosity for op prevents the increase of macrophage numbers in quadriceps nerves of the myelin mutants (P0+/− op/op). In the nondemyelinating saphenous nerves, the number of macrophages is never increased. Bars indicate mean values ± SD. *P < 0.05.
Mentions: In the quadriceps nerve of M-CSF–deficient, P0 heterozygous mice (P0+/− op/op), the number of macrophages was not increased compared with mice with normal P0 dosage (P0+/+ op/wt and P0+/+ op/op; Fig. 4). In contrast, and similar to the findings obtained from P0+/− mice (Fig. 1 C), the number of macrophages in the quadriceps nerve was strongly elevated in P0+/− op/wt mice compared with op mutants with normal P0 gene dosage (P0+/+ op/wt and P0+/+ op/op mice; P = 0.01; Fig. 4). Thus, homozygous deficiency in M-CSF leads to a lack of an age-dependent macrophage increase in the motor nerves of P0+/− mutants.

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