MCP-1/CCL2 modifies axon properties in a PMP22-overexpressing mouse model for Charcot-Marie-tooth 1A neuropathy.
Charcot-Marie-Tooth 1A (CMT1A) neuropathy, the most common inherited peripheral neuropathy, is primarily caused by a gene duplication for the peripheral myelin protein-22 (PMP22). In an accordant mouse model, we investigated the role of monocyte chemoattractant protein-1 (MCP-1/CCL2) as a regulator of nerve macrophages and neural damage including axonopathy and demyelination. By generating PMP22tg mice with reduced levels or lack of MCP-1/CCL2, we found that MCP-1/CCL2 is involved in the increase of macrophages in mutant nerves. PMP22tg mice with wild-type levels of MCP-1/CCL2 showed strong macrophage increase in the diseased nerves, whereas either 50% reduction or total absence of MCP-1/CCL2 led to a moderate or a strong reduction of nerve macrophages, respectively. Interestingly, MCP-1/CCL2 expression level and macrophage numbers were correlated with features indicative of axon damage, such as maldistribution of K+ channels, reduced compound muscle action potentials, and muscle weakness. Demyelinating features, however, were most highly reduced when MCP-1/CCL2 was diminished by 50%, whereas complete lack of MCP-1/CCL2 showed an intermediate demyelinating phenotype. We also identified the MEK1/2-ERK1/2-pathway as being involved in MCP-1/CCL2 expression in the Schwann cells of the CMT1A model. Our data show that, in a CMT1A model, MCP-1/CCL2 activates nerve macrophages, mediates both axon damage and demyelination, and may thus be a promising target for therapeutic approaches.
Kohl
Bianca
B
Department of Neurology University of Wuerzburg, Josef Schneider Strasse 11, 97080 Wuerzburg, Germany.
Fischer
Stefan
S
Groh
Janos
J
Wessig
Carsten
C
Martini
Rudolf
R
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D002452:Cell Count; D002607:Charcot-Marie-Tooth Disease / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005267:Femoral Nerve / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D018737:Hand Strength / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009185:Myelin Proteins / Q000378:metabolism*; D009186:Myelin Sheath / Q000473:pathology; D015221:Potassium Channels / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D018932:Chemokine CCL2; D009185:Myelin Proteins; C073687:PMP22 protein, human; D015221:Potassium Channels; D012333:RNA, Messenger; D048049:Extracellular Signal-Regulated MAP Kinases