Monocyte chemoattractant protein-1 is a pathogenic component in a model for a hereditary peripheral neuropathy.
Macrophages are critically involved in the pathogenesis of genetically caused demyelination, as it occurs in models for inherited demyelinating neuropathies. It is presently unknown which factors link the Schwann cell-based myelin mutation to the activation of endoneurial macrophages. Here we identified the chemokine monocyte chemoattractant protein-1 (MCP-1) as a first and crucial factor upregulated in Schwann cells of mice heterozygously deficient for the myelin protein zero. The chemokine could be identified as an important mediator of macrophage immigration into peripheral nerves. Furthermore, a 50% reduction of chemokine expression by crossbreeding with MCP-1-deficient mice reduced the increase in macrophage numbers in the mutant nerves and lead to a robust amelioration of pathology. Surprisingly, the complete absence of MCP-1 aggravated the disease. Our findings show that reducing but not eliminating chemokine expression can rescue genetically caused demyelination that may be an interesting target in treating demyelinating diseases of the peripheral nervous system.
Fischer
Stefan
S
Department of Neurology, Developmental Neurobiology, University of Wuerzburg, Wuerzburg, Germany.
Kleinschnitz
Christoph
C
Müller
Marcus
M
Kobsar
Igor
I
Ip
Chi Wang
CW
Rollins
Barrett
B
Martini
Rudolf
R
D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000235:genetics; D004195:Disease Models, Animal; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018993:Myelin P0 Protein / Q000235:genetics; D009186:Myelin Sheath / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010525:Peripheral Nerves / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000276:immunology* / Q000503:physiopathology; D011129:Polyradiculoneuropathy / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D012583:Schwann Cells / Q000276:immunology* / Q000378:metabolism
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018925:Chemokines; D018993:Myelin P0 Protein