title: Macrophage colony stimulating factor is a crucial factor for the intrinsic macrophage response in mice heterozygously deficient for the myelin protein P0.
abstract: Mouse mutants heterozygously deficient for the myelin protein P0 (P0+/-) resemble certain forms of human hereditary neuropathies. Endoneurial macrophages of intrinsic origin are intimately involved in the pathogenesis of the demyelinating neuropathy in these mutants. We have previously shown that deficiency for macrophage colony stimulating factor (M-CSF) prevents an increase of the number of endoneurial macrophages and alleviates the mutants' demyelinating phenotype. The aim of this study was to investigate which population of endoneurial macrophages - long-term resident macrophages or recently infiltrated macrophages - is affected by M-CSF deficiency. For this purpose, we generated bone marrow chimeric mice by transplanting GFP+ bone marrow into P0 mutants (P0+/-) and P0 mutants that lack M-CSF (P0+/- mcsf-op). This enabled us to discriminate recently infiltrated short-term resident GFP+ macrophages from long-term resident GFP- macrophages. Three months after bone marrow transplantation, P0+/- mice expressing M-CSF showed a substantial upregulation and activation of both GFP- and GFP+ macrophages in femoral nerves when compared to P0+/+ mice. In contrast, in P0+/- mcsf-op mutants, both GFP- and GFP+ macrophages did not substantially increase. Only small numbers of GFP+ but no GFP- macrophages were activated and phagocytosed myelin in chimeric P0+/- mcsf-op mutants, possibly reflecting recent activation outside the endoneurium before entering the nerve. Our findings demonstrate that M-CSF is crucial for the activation, in situ increase and myelin phagocytosis of both long-term and short-term resident endoneurial macrophages in P0+/- myelin mutants. M-CSF is, therefore, considered as a target candidate for therapeutic strategies to treat human demyelinating neuropathies.
authors.affiliation: Department of Neurology, University of Münster, Albert-Schweitzer-Str. 33, D-48129 Münster, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Müller
authors.forename: Martin
authors.initials: M
authors.lastname: Berghoff
authors.forename: Igor
authors.initials: I
authors.lastname: Kobsar
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kiefer
authors.forename: Rudolf
authors.initials: R
authors.lastname: Martini
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006579:Heterozygote; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D018993:Myelin P0 Protein / Q000235:genetics*; D009186:Myelin Sheath / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D010525:Peripheral Nerves / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology / Q000648:ultrastructure; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D011129:Polyradiculoneuropathy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D018183:Transplantation Chimera; D015854:Up-Regulation / Q000502:physiology
chemical_list: D018993:Myelin P0 Protein; D049452:Green Fluorescent Proteins; D016173:Macrophage Colony-Stimulating Factor