The role of macrophages in demyelinating peripheral nervous system of miceheterozygously deficient in P0

Mice heterozygously deficient in the p0 gene (P0(+/-)) are animal models fo r some forms of inherited neuropathies. They display a progressive demyelin ating phenotype in motor nerves, accompanied by mild infiltration of lympho cytes and increase in macrophages, We have shown previously that the T lymp hocytes 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 moto r nerves of wild-type mice. Immunoelectron microscopy, using a specific mar ker for mouse macrophages, displayed macrophages not only in the endoneuriu m of the myelin mutants, but also within endoneurial tubes, suggesting an a ctive role in demyelination. To elucidate the roles of the macrophages, we crossbred the myelin mutants with a spontaneous mouse mutant deficient in m acrophage colony-stimulating factor (M-CSF), hence displaying impaired macr ophage activation. In the P0-deficient double mutants also deficient in M-C SF, the numbers of macrophages Mere not elevated in the demyelinating motor nerves and demyelination was less severe. These findings demonstrate an ac tive role of macrophages during pathogenesis of inherited demyelination wit h putative impact on future treatment strategies.