title: Down-regulation of neuronal L1 cell adhesion molecule expression alleviates inflammatory neuronal injury.
abstract: In multiple sclerosis (MS), the immune cell attack leads to axonal injury as a major cause for neurological disability. Here, we report a novel role of the cell adhesion molecule L1 in the crosstalk between the immune and nervous systems. L1 was found to be expressed by CNS axons of MS patients and human T cells. In MOG35-55-induced murine experimental neuroinflammation, CD4+T cells were associated with degenerating axons in the spinal cord, both expressing L1. However, neuronal L1 expression in the spinal cord was reduced, while levels of the transcriptional repressor REST (RE1-Silencing Transcription Factor) were up-regulated. In PLP139-151-induced relapsing-remitting neuroinflammation, L1 expression was low at the peak stage of disease, reached almost normal levels in the remission stage, but decreased again during disease relapse indicating adaptive expression regulation of L1. In vitro, activated CD4+T cells caused contact-dependent down-regulation of L1, up-regulation of its repressor REST and axonal injury in co-cultured neurons. T cell adhesion to neurons and axonal injury were prevented by an antibody blocking L1 suggesting that down-regulation of L1 ameliorates neuroinflammation. In support of this hypothesis, antibody-mediated blocking of L1 in C57BL/6 mice as well as neuron-specific depletion of L1 in synapsinCre× L1fl/flmice reduces disease severity and axonal pathology despite unchanged immune cell infiltration of the CNS. Our data suggest that down-regulation of neuronal L1 expression is an adaptive process of neuronal self-defense in response to pro-inflammatory T cells, thereby alleviating immune-mediated axonal injury.
authors.affiliation: Department of Anesthesiology, University Medical Center of the Johannes-Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Menzel
authors.affiliation: Department of Neurology, University Medical Center of the Johannes-Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Paterka
authors.affiliation: Department of Neurology, University Medical Center of the Johannes-Gutenberg-University Mainz, Mainz, Germany.|Focus Program Translational Neuroscience (FTN) and Rhine Main Neuroscience Network (rmn²), Mainz, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bittner
authors.affiliation: Institute of Physiology, University Medical Center of the Johannes-Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Robin
authors.initials: R
authors.lastname: White
authors.affiliation: Department of Anesthesiology, University Medical Center of the Johannes-Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Wiesia
authors.initials: W
authors.lastname: Bobkiewicz
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Jack
authors.initials: J
authors.lastname: van Horssen
authors.affiliation: Center for Neuroscience, Shantou University Medical College, Shantou, China.
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
authors.affiliation: Department of Neurology, University Medical Center of the Johannes-Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Witsch
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Kuhlmann
authors.affiliation: Department of Neurology, University Medical Center of the Johannes-Gutenberg-University Mainz, Mainz, Germany.|Focus Program Translational Neuroscience (FTN) and Rhine Main Neuroscience Network (rmn²), Mainz, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Zipp
authors.affiliation: Department of Anesthesiology, University Medical Center of the Johannes-Gutenberg-University Mainz, Mainz, Germany. michael.schaefer@unimedizin-mainz.de.|Focus Program Translational Neuroscience (FTN) and Rhine Main Neuroscience Network (rmn²), Mainz, Germany. michael.schaefer@unimedizin-mainz.de.
authors.forename: Michael K E
authors.identifier: 0000-0001-6055-6244
authors.initials: MK
authors.lastname: Schäfer
mesh_terms: D000368:Aged; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D018920:Coculture Techniques; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D018991:Myelin Proteolipid Protein / Q000494:pharmacology; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D016704:Synapsins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology*
chemical_list: D018991:Myelin Proteolipid Protein; D063308:Myelin-Oligodendrocyte Glycoprotein; D009419:Nerve Tissue Proteins; D039842:Neural Cell Adhesion Molecule L1; D010446:Peptide Fragments; D016704:Synapsins; C445081:myelin oligodendrocyte glycoprotein (35-55); C435023:myelin proteolipid protein (139-151)
keywords: Axonal injury; EAE; L1CAM; Multiple sclerosis; Neuroinflammation; T cells