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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) Immunhistological localization of macrophages in quadriceps nerves of P0+/+ (A) and P0+/− mice (B) at the age of 6 mo using antibodies to F4/80. (A) In quadriceps nerves of P0+/+ mice some resident macrophages are detectable in the endoneurium. (B) In quadriceps nerves of P0+/− mice the number of macrophages is clearly elevated when compared with P0+/+ mice. Note the larger size of the cells and the close vicinity of two cells to an endoneurial blood vessel. (C) Quantification of F4/80-positive macrophages in quadriceps and saphenous nerves of P0+/+ (black bars) and P0+/− mice (gray bars) at the age of 2 (n = 2 for P0+/+ and P0+/−), 6 (n = 3 for P0+/+; n = 4 for P0+/−), and 12 mo (n = 4 for P0+/+ and P0+/−). Note elevated number of macrophages in quadriceps nerves of 6- and 12-mo-old P0+/− mice. A slight elevation of macrophage numbers is already seen in quadriceps nerves of 2-mo-old P0+/− mice. In nondemyelinating saphenous nerves, the number of macrophages is not increased at any age investigated. Bars represent mean values ± SD. *P < 0.05; ***P < 0.001. Bar, 50 μm.
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Figure 1: (A and B) Immunhistological localization of macrophages in quadriceps nerves of P0+/+ (A) and P0+/− mice (B) at the age of 6 mo using antibodies to F4/80. (A) In quadriceps nerves of P0+/+ mice some resident macrophages are detectable in the endoneurium. (B) In quadriceps nerves of P0+/− mice the number of macrophages is clearly elevated when compared with P0+/+ mice. Note the larger size of the cells and the close vicinity of two cells to an endoneurial blood vessel. (C) Quantification of F4/80-positive macrophages in quadriceps and saphenous nerves of P0+/+ (black bars) and P0+/− mice (gray bars) at the age of 2 (n = 2 for P0+/+ and P0+/−), 6 (n = 3 for P0+/+; n = 4 for P0+/−), and 12 mo (n = 4 for P0+/+ and P0+/−). Note elevated number of macrophages in quadriceps nerves of 6- and 12-mo-old P0+/− mice. A slight elevation of macrophage numbers is already seen in quadriceps nerves of 2-mo-old P0+/− mice. In nondemyelinating saphenous nerves, the number of macrophages is not increased at any age investigated. Bars represent mean values ± SD. *P < 0.05; ***P < 0.001. Bar, 50 μm.

Mentions: In nerve cross sections of normal mice, the F4/80 immunoperoxidase-positive macrophages were usually ramified or showed a few slender processes (Fig. 1A and Fig. B). Most, if not all, F4/80-immunoreactive macrophages in the quadriceps nerve and ventral root were MHC class II–positive, as revealed by double immunofluorescence (not shown). By contrast, MHC class I immunoreactivity was confined to nonmyelinating Schwann cells, as revealed by double immunofluorescence with antibodies to neural cell adhesion molecule, recognizing nonmyelinating Schwann cells in peripheral nerves (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) Immunhistological localization of macrophages in quadriceps nerves of P0+/+ (A) and P0+/− mice (B) at the age of 6 mo using antibodies to F4/80. (A) In quadriceps nerves of P0+/+ mice some resident macrophages are detectable in the endoneurium. (B) In quadriceps nerves of P0+/− mice the number of macrophages is clearly elevated when compared with P0+/+ mice. Note the larger size of the cells and the close vicinity of two cells to an endoneurial blood vessel. (C) Quantification of F4/80-positive macrophages in quadriceps and saphenous nerves of P0+/+ (black bars) and P0+/− mice (gray bars) at the age of 2 (n = 2 for P0+/+ and P0+/−), 6 (n = 3 for P0+/+; n = 4 for P0+/−), and 12 mo (n = 4 for P0+/+ and P0+/−). Note elevated number of macrophages in quadriceps nerves of 6- and 12-mo-old P0+/− mice. A slight elevation of macrophage numbers is already seen in quadriceps nerves of 2-mo-old P0+/− mice. In nondemyelinating saphenous nerves, the number of macrophages is not increased at any age investigated. Bars represent mean values ± SD. *P < 0.05; ***P < 0.001. Bar, 50 μm.
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Related In: Results  -  Collection

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Figure 1: (A and B) Immunhistological localization of macrophages in quadriceps nerves of P0+/+ (A) and P0+/− mice (B) at the age of 6 mo using antibodies to F4/80. (A) In quadriceps nerves of P0+/+ mice some resident macrophages are detectable in the endoneurium. (B) In quadriceps nerves of P0+/− mice the number of macrophages is clearly elevated when compared with P0+/+ mice. Note the larger size of the cells and the close vicinity of two cells to an endoneurial blood vessel. (C) Quantification of F4/80-positive macrophages in quadriceps and saphenous nerves of P0+/+ (black bars) and P0+/− mice (gray bars) at the age of 2 (n = 2 for P0+/+ and P0+/−), 6 (n = 3 for P0+/+; n = 4 for P0+/−), and 12 mo (n = 4 for P0+/+ and P0+/−). Note elevated number of macrophages in quadriceps nerves of 6- and 12-mo-old P0+/− mice. A slight elevation of macrophage numbers is already seen in quadriceps nerves of 2-mo-old P0+/− mice. In nondemyelinating saphenous nerves, the number of macrophages is not increased at any age investigated. Bars represent mean values ± SD. *P < 0.05; ***P < 0.001. Bar, 50 μm.
Mentions: In nerve cross sections of normal mice, the F4/80 immunoperoxidase-positive macrophages were usually ramified or showed a few slender processes (Fig. 1A and Fig. B). Most, if not all, F4/80-immunoreactive macrophages in the quadriceps nerve and ventral root were MHC class II–positive, as revealed by double immunofluorescence (not shown). By contrast, MHC class I immunoreactivity was confined to nonmyelinating Schwann cells, as revealed by double immunofluorescence with antibodies to neural cell adhesion molecule, recognizing nonmyelinating Schwann cells in peripheral nerves (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