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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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Conventional electron microscopy (A and B) and immunoelectron microscopy using the macrophage-specific antibody F4/80 (C and D) in quadriceps nerves of 6-mo-old P0+/− mice. (A) A putative macrophage (m) that is laden with myelin debris is closely apposed to a demyelinated axon (a). Note the slender processes of the macrophage (arrows) and the position of the cell within the endoneurial tube. The arrowheads demarcate the Schwann cell basal lamina. (B) A putative macrophage (m) is in close contact to a thin myelin sheath that is partially detached from the corresponding axon (a). The arrow demarcates a process of the putative macrophage that penetrates the Schwann cell basal lamina. Sc, Schwann cell. (C) An F4/80-positive macrophage (m) containing myelin debris is in close apposition to a myelin sheath. Arrowheads indicate electron-dense immunoreaction product. a, Axon; Sc, Schwann cell. (D) A slender process of a F4/80-positive macrophage (m) has penetrated in between the pericaryon of the Schwann cell (Sc) and its normal appearing myelin sheath. Arrowheads indicate electron-dense immunoreaction product. a, axon. Bars, 1.5 μm.
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Figure 3: Conventional electron microscopy (A and B) and immunoelectron microscopy using the macrophage-specific antibody F4/80 (C and D) in quadriceps nerves of 6-mo-old P0+/− mice. (A) A putative macrophage (m) that is laden with myelin debris is closely apposed to a demyelinated axon (a). Note the slender processes of the macrophage (arrows) and the position of the cell within the endoneurial tube. The arrowheads demarcate the Schwann cell basal lamina. (B) A putative macrophage (m) is in close contact to a thin myelin sheath that is partially detached from the corresponding axon (a). The arrow demarcates a process of the putative macrophage that penetrates the Schwann cell basal lamina. Sc, Schwann cell. (C) An F4/80-positive macrophage (m) containing myelin debris is in close apposition to a myelin sheath. Arrowheads indicate electron-dense immunoreaction product. a, Axon; Sc, Schwann cell. (D) A slender process of a F4/80-positive macrophage (m) has penetrated in between the pericaryon of the Schwann cell (Sc) and its normal appearing myelin sheath. Arrowheads indicate electron-dense immunoreaction product. a, axon. Bars, 1.5 μm.

Mentions: In ultrathin sections of conventionally prepared quadriceps nerves and ventral roots, endoneurial cells laden with lipid vacuoles or myelin debris were identified as macrophages. They were often found in the endoneurium and were characterized by polymorphic nuclei, abundant heterochromatin, and microvillus-like processes that extended from the surface. Occasionally, such cells were found in the endoneurial tubes, i.e., within the Schwann cell basal laminae (Fig. 3A and Fig. B). In very rare cases, macrophage-like cells were seen just penetrating the basal lamina with a cellular process, reflecting the invasion or leave of the endoneurial tube (Fig. 3 B). However, since Schwann cells can also phagocytose myelin and penetrate basal laminae under pathological conditions, morphological criteria alone appeared insufficient to characterize unequivocally the spatial relationship between macrophages and nerve fibers. Therefore, we performed immunoelectron microscopy using the macrophage-specific antibody F4/80.


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)

Conventional electron microscopy (A and B) and immunoelectron microscopy using the macrophage-specific antibody F4/80 (C and D) in quadriceps nerves of 6-mo-old P0+/− mice. (A) A putative macrophage (m) that is laden with myelin debris is closely apposed to a demyelinated axon (a). Note the slender processes of the macrophage (arrows) and the position of the cell within the endoneurial tube. The arrowheads demarcate the Schwann cell basal lamina. (B) A putative macrophage (m) is in close contact to a thin myelin sheath that is partially detached from the corresponding axon (a). The arrow demarcates a process of the putative macrophage that penetrates the Schwann cell basal lamina. Sc, Schwann cell. (C) An F4/80-positive macrophage (m) containing myelin debris is in close apposition to a myelin sheath. Arrowheads indicate electron-dense immunoreaction product. a, Axon; Sc, Schwann cell. (D) A slender process of a F4/80-positive macrophage (m) has penetrated in between the pericaryon of the Schwann cell (Sc) and its normal appearing myelin sheath. Arrowheads indicate electron-dense immunoreaction product. a, axon. Bars, 1.5 μm.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Conventional electron microscopy (A and B) and immunoelectron microscopy using the macrophage-specific antibody F4/80 (C and D) in quadriceps nerves of 6-mo-old P0+/− mice. (A) A putative macrophage (m) that is laden with myelin debris is closely apposed to a demyelinated axon (a). Note the slender processes of the macrophage (arrows) and the position of the cell within the endoneurial tube. The arrowheads demarcate the Schwann cell basal lamina. (B) A putative macrophage (m) is in close contact to a thin myelin sheath that is partially detached from the corresponding axon (a). The arrow demarcates a process of the putative macrophage that penetrates the Schwann cell basal lamina. Sc, Schwann cell. (C) An F4/80-positive macrophage (m) containing myelin debris is in close apposition to a myelin sheath. Arrowheads indicate electron-dense immunoreaction product. a, Axon; Sc, Schwann cell. (D) A slender process of a F4/80-positive macrophage (m) has penetrated in between the pericaryon of the Schwann cell (Sc) and its normal appearing myelin sheath. Arrowheads indicate electron-dense immunoreaction product. a, axon. Bars, 1.5 μm.
Mentions: In ultrathin sections of conventionally prepared quadriceps nerves and ventral roots, endoneurial cells laden with lipid vacuoles or myelin debris were identified as macrophages. They were often found in the endoneurium and were characterized by polymorphic nuclei, abundant heterochromatin, and microvillus-like processes that extended from the surface. Occasionally, such cells were found in the endoneurial tubes, i.e., within the Schwann cell basal laminae (Fig. 3A and Fig. B). In very rare cases, macrophage-like cells were seen just penetrating the basal lamina with a cellular process, reflecting the invasion or leave of the endoneurial tube (Fig. 3 B). However, since Schwann cells can also phagocytose myelin and penetrate basal laminae under pathological conditions, morphological criteria alone appeared insufficient to characterize unequivocally the spatial relationship between macrophages and nerve fibers. Therefore, we performed immunoelectron microscopy using the macrophage-specific antibody F4/80.

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