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Increase of MCP‐1 (CCL2) in myelin mutant Schwann cells is mediated by MEK‐ERK signaling pathway
Author(s) -
Fischer Stefan,
Weishaupt Andreas,
Troppmair Jakob,
Martini Rudolf
Publication year - 2008
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.20657
Subject(s) - schwann cell , microbiology and biotechnology , biology , mapk/erk pathway , myelin , kinase , signal transduction , mitogen activated protein kinase , phosphorylation , intracellular , neuroscience , central nervous system
Macrophages are critically involved in the pathogenesis of genetically caused demyelination, as it occurs in inherited demyelinating neuropathies. On the basis of the observation that upregulation of the Schwann cell‐derived chemokine MCP‐1 (CCL2) is a pathologically relevant mechanism for macrophage activation in mice heterozygously deficient for the myelin component P0 (P0+/−), we posed the question of the intracellular signaling cascade involved. By using western blot analysis of peripheral nerve lysates the MAP‐kinases extracellular signal‐regulated kinase 1/2 (ERK1/2) and MAP kinase/ERK kinase 1/2 (MEK1/2) showed an early and constantly increasing activation in P0 mutants. Furthermore, in nerve fibers from the P0+/− mutants, Schwann cell nuclei were much more often positive for phosphorylated ERK1/2 than in nerve fibers from wild type mice. In vitro experiments using the MEK1/2‐inhibitor CI‐1040 decreased ERK1/2‐phosphorylation and MCP‐1 expression in a Schwann cell‐derived cell line. Finally, systemic application of CI‐1040 lead to a decreased ERK1/2‐phosphorylation and substantially reduced MCP‐1‐production in peripheral nerves of P0+/− mutant mice. Our study identifies MEK1/2‐ERK1/2 signaling as an important intracellular pathway that connects the Schwann cell mutation with the activation of pathogenetically relevant macrophages in the peripheral nerves. These findings may have important implications for the treatment of inherited peripheral neuropathies in humans. © 2008 Wiley‐Liss, Inc.