Sialoadhesin deficiency ameliorates myelin degeneration and axonopathic changes in the CNS of PLP overexpressing mice.
PLP overexpressing mice display demyelination and axonopathic changes, accompanied by an elevation of CD8+ T-lymphocytes and CD11b+ macrophages in the CNS. By crossbreeding these mutants with RAG-1-deficient mice lacking mature lymphocytes, we could recently demonstrate a pathogenetic impact of the CD8+ cells. In the present study, we investigated the pathogenetic impact of CD11b+ macrophages by crossbreeding the myelin mutants with knockout mice deficient for the macrophage-restricted adhesion molecule sialoadhesin (Sn). In the wild-type mice, Sn is barely detectable on CD11b+ cells, whereas in the myelin mutants, almost all CD11b+ cells express Sn. In the double mutants, upregulation of CD8+ T-cells and CD11b+ macrophages is reduced and pathological alterations are ameliorated. These data indicate that in a primarily genetically caused myelin disorder of the CNS macrophages expressing Sn partially mediate pathogenesis. These findings may have substantial impact on treatment strategies for leukodystrophic disorders and some forms of multiple sclerosis.
Ip
Chi Wang
CW
Department of Neurology, Section of Developmental Neurobiology, University of Wuerzburg, Josef-Schneider Str. 11, D-97080 Wuerzburg, Germany.
Kroner
Antje
A
Crocker
Paul R
PR
Nave
Klaus-Armin
KA
Martini
Rudolf
R
D000818:Animals; D001369:Axons / Q000473:pathology* / Q000502:physiology; D039481:CD11b Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002490:Central Nervous System / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D005838:Genotype; D007150:Immunohistochemistry; D008264:Macrophages / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology*; D010740:Phospholipases / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology*; D063267:Sialic Acid Binding Ig-like Lectin 1
D039481:CD11b Antigen; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D063267:Sialic Acid Binding Ig-like Lectin 1; C571167:Siglec1 protein, mouse; D010740:Phospholipases