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Acta Neuropathologica
Published in: Acta Neuropathologica 5/2016

01-11-2016 | Original Paper

Down-regulation of neuronal L1 cell adhesion molecule expression alleviates inflammatory neuronal injury

Authors: Lutz Menzel, Magdalena Paterka, Stefan Bittner, Robin White, Wiesia Bobkiewicz, Jack van Horssen, Melitta Schachner, Esther Witsch, Tanja Kuhlmann, Frauke Zipp, Michael K. E. Schäfer

Published in: Acta Neuropathologica | Issue 5/2016

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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/fl mice 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.
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Literature
1.
Appel F, Holm J, Conscience JF, von Bohlen F, Faissner A, James P, Schachner M (1995) Identification of the border between fibronectin type III homologous repeats 2 and 3 of the neural cell adhesion molecule L1 as a neurite outgrowth promoting and signal transducing domain. J Neurobiol 28:297–312CrossRefPubMed
2.
Balaian LB, Moehler T, Montgomery AMP (2000) The human neural cell adhesion molecule L1 functions as a costimulatory molecule in T cell activation. Eur J Immunol 30:938–943CrossRefPubMed
3.
Bechara A, Nawabi H, Moret F, Yaron A, Weaver E, Bozon M, Abouzid K, Guan J-L, Tessier-Lavigne M, Lemmon V, Castellani V (2008) FAK-MAPK-dependent adhesion disassembly downstream of L1 contributes to semaphorin3A-induced collapse. EMBO J 27:1549–1562CrossRefPubMedPubMedCentral
4.
Ben-Nun A, Kaushansky N, Kawakami N, Krishnamoorthy G, Berer K, Liblau R, Hohlfeld R, Wekerle H (2014) From classic to spontaneous and humanized models of multiple sclerosis: Impact on understanding pathogenesis and drug development. J Autoimmun 54:33–50CrossRefPubMed
5.
Ben-Zvi A, Manor O, Schachner M, Yaron A, Tessier-Lavigne M, Behar O (2008) The semaphorin receptor plexinA3 mediates neuronal apoptosis during dorsal root ganglia development. J Neurosci 28:12427–12432CrossRefPubMed
6.
Brewer GJ, Price PJ (1996) Viable cultured neurons in ambient carbon dioxide and hibernation storage for a month. NeuroReport 7:1509–1512CrossRefPubMed
7.
Calderone A, Jover T, K-m Noh, Tanaka H, Yokota H, Lin Y, Grooms SY, Regis R, Bennett MVL, Zukin RS (2003) Ischemic insults derepress the gene silencer REST in neurons destined to die. J Neurosci 23:2112–2121PubMed
8.
Castellani V, De Angelis E, Kenwrick S, Rougon G (2002) Cis and trans interactions of L1 with neuropilin-1 control axonal responses to semaphorin 3A. EMBO J 21:6348–6357CrossRefPubMedPubMedCentral
9.
Christaller WA, Vos Y, Gebre-Medhin S, Hofstra RM, Schafer MK (2016) L1 syndrome diagnosis complemented with functional analysis of L1CAM variants located to the two N-terminal Ig-like domains. Clin Genet. doi:10.​1111/​cge.​12763 PubMed
10.
Cohen NR, Taylor JSH, Scott LB, Guillery RW, Soriano P, Furley AJW (1998) Errors in corticospinal axon guidance in mice lacking the neural cell adhesion molecule L1. Curr Biol 8:26–33CrossRefPubMed
11.
Dahme M, Bartsch U, Martini R, Anliker B, Schachner M, Mantei N (1997) Disruption of the mouse L1 gene leads to malformations of the nervous system. Nat Genet 17:346–349CrossRefPubMed
12.
De Gasperi R, Rocher AB, Sosa MAG, Wearne SL, Perez GM, Friedrich VL, Hof PR, Elder GA (2008) The IRG mouse: a two-color fluorescent reporter for assessing Cre-mediated recombination and imaging complex cellular relationships in situ. Genesis 46:308–317CrossRefPubMedPubMedCentral
13.
Derfuss T, Parikh K, Velhin S, Braun M, Mathey E, Krumbholz M, Kümpfel T, Moldenhauer A, Rader C, Sonderegger P, Pöllmann W, Tiefenthaller C, Bauer J, Lassmann H, Wekerle H, Karagogeos D, Hohlfeld R, Linington C, Meinl E (2009) Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals. Proc Natl Acad Sci USA 106:8302–8307CrossRefPubMedPubMedCentral
14.
Ebeling O, Duczmal A, Aigner S, Geiger C, Schöllhammer S, Kemshead JT, Möller P, Schwartz-Albiez R, Altevogt P (1996) L1 adhesion molecule on human lymphocytes and monocytes: expression and involvement in binding to αvβ3 integrin. Eur J Immunol 26:2508–2516CrossRefPubMed
15.
Formisano L, Guida N, Laudati G, Boscia F, Esposito A, Secondo A, Di Renzo G, Canzoniero LM (2015) Extracellular signal-related kinase 2/specificity protein 1/specificity protein 3/repressor element-1 silencing transcription factor pathway is involved in Aroclor 1254-induced toxicity in SH-SY5Y neuronal cells. J Neurosci Res 93:167–177CrossRefPubMed
16.
Fransen E, D’Hooge R, Van Camp G, Verhoye M, Sijbers J, Reyniers E, Soriano P, Kamiguchi H, Willemsen R, Koekkoek SKE, De Zeeuw CI, De Deyn PP, Van der Linden A, Lemmon V, Kooy RF, Willems PJ (1998) L1 knockout mice show dilated ventricles, vermis hypoplasia and impaired exploration patterns. Hum Mol Genet 7:999–1009CrossRefPubMed
17.
Irintchev A, Schachner M (2012) The injured and regenerating nervous system: immunoglobulin superfamily members as key players. Neuroscientist 18:452–466CrossRefPubMed
18.
Islam R, Kristiansen LV, Romani S, Garcia-Alonso L, Hortsch M (2004) Activation of EGF receptor kinase by L1-mediated homophilic cell interactions. Mol Biol Cell 15:2003–2012CrossRefPubMedPubMedCentral
19.
Jakeman LB, Chen Y, Lucin KM, McTigue DM (2006) Mice lacking L1 cell adhesion molecule have deficits in locomotion and exhibit enhanced corticospinal tract sprouting following mild contusion injury to the spinal cord. Eur J Neurosci 23:1997–2011CrossRefPubMed
20.
Jakovcevski I, Djogo N, Hölters LS, Szpotowicz E, Schachner M (2013) Transgenic overexpression of the cell adhesion molecule L1 in neurons facilitates recovery after mouse spinal cord injury. Neuroscience 252:1–12CrossRefPubMed
21.
Jolivel V, Luessi F, Masri J, Kraus SHP, Hubo M, Poisa-Beiro L, Klebow S, Paterka M, Yogev N, Tumani H, Furlan R, Siffrin V, Jonuleit H, Zipp F, Waisman A (2013) Modulation of dendritic cell properties by laquinimod as a mechanism for modulating multiple sclerosis. Brain 136:1048–1066. doi:10.​1093/​brain/​awt023 CrossRefPubMed
22.
Jonas A, Thiem S, Kuhlmann T, Wagener R, Aszodi A, Nowell C, Hagemeier K, Laverick L, Perreau V, Jokubaitis V, Emery B, Kilpatrick T, Butzkueven H, Gresle M (2014) Axonally derived matrilin-2 induces proinflammatory responses that exacerbate autoimmune neuroinflammation. J Clin Invest 124:5042–5056CrossRefPubMedPubMedCentral
23.
Jouet M, Rosenthal A, Kenwrick S (1995) Exon 2 of the gene for neural cell adhesion molecule L1 is alternatively spliced in B cells. Brain Res Mol Brain Res 30:378–380CrossRefPubMed
24.
25.
26.
Kataria H, Lutz D, Chaudhary H, Schachner M, Loers G (2015) Small molecule agonists of cell adhesion molecule L1 mimic L1 functions in vivo. Mol Neurobiol 1–23. doi:10.​1007/​s12035-015-9352-6
27.
28.
Law JWS, Lee AYW, Sun M, Nikonenko AG, Chung SK, Dityatev A, Schachner M, Morellini F (2003) Decreased anxiety, altered place learning, and increased CA1 basal excitatory synaptic transmission in mice with conditional ablation of the neural cell adhesion molecule L1. J Neurosci 23:10419–10432PubMed
29.
Lepelletier Y, Moura IC, Hadj-Slimane R, Renand A, Fiorentino S, Baude C, Shirvan A, Barzilai A, Hermine O (2006) Immunosuppressive role of semaphorin-3A on T cell proliferation is mediated by inhibition of actin cytoskeleton reorganization. Eur J Immunol 36:1782–1793CrossRefPubMed
30.
Leuenberger T, Paterka M, Reuter E, Herz J, Niesner RA, Radbruch H, Bopp T, Zipp F, Siffrin V (2013) The role of CD8 + T cells and their local interaction with CD4 + T cells in myelin oligodendrocyte glycoprotein35–55-induced experimental autoimmune encephalomyelitis. J Immunol 191:4960–4968. doi:10.​4049/​jimmunol.​1300822 CrossRefPubMed
31.
Liblau RS, Gonzalez-Dunia D, Wiendl H, Zipp F (2013) Neurons as targets for T cells in the nervous system. Trends Neurosci 36:315–324CrossRefPubMed
32.
Maddaluno L, Verbrugge SE, Martinoli C, Matteoli G, Chiavelli A, Zeng Y, Williams ED, Rescigno M, Cavallaro U (2009) The adhesion molecule L1 regulates transendothelial migration and trafficking of dendritic cells. J Exp Med 206:623–635CrossRefPubMedPubMedCentral
33.
Maness PF, Schachner M (2007) Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon guidance and neuronal migration. Nat Neurosci 10:19–26CrossRefPubMed
34.
Marx M, Diestel S, Bozon M, Keglowich L, Drouot N, Bouché E, Frebourg T, Minz M, Saugier-Veber P, Castellani V, Schäfer M (2012) Pathomechanistic characterization of two exonic L1CAM variants located in trans in an obligate carrier of X-linked hydrocephalus. Neurogenetics 13:49–59CrossRefPubMed
35.
Mathey EK, Derfuss T, Storch MK, Williams KR, Hales K, Woolley DR, Al-Hayani A, Davies SN, Rasband MN, Olsson T, Moldenhauer A, Velhin S, Hohlfeld R, Meinl E, Linington C (2007) Neurofascin as a novel target for autoantibody-mediated axonal injury. J Exp Med 204:2363–2372. doi:10.​1084/​jem.​20071053 CrossRefPubMedPubMedCentral
36.
Mechtersheimer S, Gutwein P, Agmon-Levin N, Stoeck A, Oleszewski M, Riedle S, Postina R, Fahrenholz F, Fogel M, Lemmon V, Altevogt P (2001) Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins. J Cell Biol 155:661–674CrossRefPubMedPubMedCentral
37.
Miller NM, Shriver LP, Bodiga VL, Ray A, Basu S, Ahuja R, Jana A, Pahan K, Dittel BN (2013) Lymphocytes with cytotoxic activity induce rapid microtubule axonal destabilization independently and before signs of neuronal death. ASN Neuro 5
38.
Nesti E, Corson GM, McCleskey M, Oyer JA, Mandel G (2014) C-terminal domain small phosphatase 1 and MAP kinase reciprocally control REST stability and neuronal differentiation. Proc Natl Acad Sci USA 111:2CrossRef
39.
Nijland PG, Michailidou I, Witte ME, Mizee MR, van der Pol SM, van Het Hof B, Reijerkerk A, Pellerin L, van der Valk P, de Vries HE, van Horssen J (2014) Cellular distribution of glucose and monocarboxylate transporters in human brain white matter and multiple sclerosis lesions. Glia 62:1125–1141. doi:10.​1002/​glia.​22667 CrossRefPubMed
40.
Nikic I, Merkler D, Sorbara C, Brinkoetter M, Kreutzfeldt M, Bareyre FM, Bruck W, Bishop D, Misgeld T, Kerschensteiner M (2011) A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med 17:495–499CrossRefPubMed
41.
Paquette AJ, Perez SE, Anderson DJ (2000) Constitutive expression of the neuron-restrictive silencer factor (NRSF)/REST in differentiating neurons disrupts neuronal gene expression and causes axon pathfinding errors in vivo. Proc Natl Acad Sci USA 97:12318–12323CrossRefPubMedPubMedCentral
42.
43.
Pozzi D, Lignani G, Ferrea E, Contestabile A, Paonessa F, D’Alessandro R, Lippiello P, Boido D, Fassio A, Meldolesi J, Valtorta F, Benfenati F, Baldelli P (2013) REST/NRSF-mediated intrinsic homeostasis protects neuronal networks from hyperexcitability. EMBO J 32:2994–3007CrossRefPubMedPubMedCentral
44.
Rathjen FG, Schachner M (1984) Immunocytological and biochemical characterization of a new neuronal cell surface component (L1 antigen) which is involved in cell adhesion. EMBO J 3:1–10PubMedPubMedCentral
45.
Roonprapunt C, Huang W, Grill R, Friedlander D, Grumet M, Chen S, Schachner M, Young W (2003) Soluble cell adhesion molecule L1-Fc promotes locomotor recovery in rats after spinal cord injury. J Neurotrauma 20:871–882CrossRefPubMed
46.
Runker AE, Bartsch U, Nave K-A, Schachner M (2003) The C264Y missense mutation in the extracellular domain of L1 impairs protein trafficking in vitro and in vivo. J Neurosci 23:277–286PubMed
47.
Ruppert M, Aigner S, Hubbe M, Yagita H, Altevogt P (1995) The L1 adhesion molecule is a cellular ligand for VLA-5. J Cell Biol 131:1881–1891CrossRefPubMed
48.
Saghatelyan AK, Nikonenko AG, Sun M, Rolf B, Putthoff P, Kutsche M, Bartsch U, Dityatev A, Schachner M (2004) Reduced GABAergic transmission and number of hippocampal perisomatic inhibitory synapses in juvenile mice deficient in the neural cell adhesion molecule L1. Mol Cell Neurosci 26:191–203CrossRefPubMed
49.
Sawma P, Roth L, Blanchard C, Bagnard D, Cremel G, Bouveret E, Duneau JP, Sturgis JN, Hubert P (2014) Evidence for new homotypic and heterotypic interactions between transmembrane helices of proteins involved in receptor tyrosine kinase and neuropilin signaling. J Mol Biol 426:4099–4111CrossRefPubMed
50.
Schäfer M, Altevogt P (2010) L1CAM malfunction in the nervous system and human carcinomas. Cell Mol Life Sci 67:2425–2437CrossRefPubMed
51.
Schäfer MKE, Frotscher M (2012) Role of L1CAM for axon sprouting and branching. Cell Tissue Res 349:39–48CrossRefPubMed
52.
Schmid J, Bernreuther C, Nikonenko A, Ling Z, Mies G, Hossmann K-A, Jakovcevski I, Schachner M (2013) Heterozygosity for the mutated X-chromosome-linked L1 cell adhesion molecule gene leads to increased numbers of neurons and enhanced metabolism in the forebrain of female carrier mice. Brain Struct Funct 218:1375–1390CrossRefPubMed
53.
Shriver LP, Dittel BN (2006) T-cell-mediated disruption of the neuronal microtubule network: correlation with early reversible axonal dysfunction in acute experimental autoimmune encephalomyelitis. Am J Pathol 169:999–1011CrossRefPubMedPubMedCentral
54.
Siffrin V, Brandt AU, Radbruch H, Herz J, Boldakowa N, Leuenberger T, Werr J, Hahner A, Schulze-Topphoff U, Nitsch R, Zipp F (2009) Differential immune cell dynamics in the CNS cause CD4 + T cell compartmentalization. Brain 132:1247–1258CrossRefPubMed
55.
Siffrin V, Radbruch H, Glumm R, Niesner R, Paterka M, Herz J, Leuenberger T, Lehmann SM, Luenstedt S, Rinnenthal JL, Laube G, Luche H, Lehnardt S, Fehling H-J, Griesbeck O, Zipp F (2010) In Vivo imaging of partially reversible Th17 cell-induced neuronal dysfunction in the course of encephalomyelitis. Immunity 33:424–436CrossRefPubMed
56.
Siffrin V, Vogt J, Radbruch H, Nitsch R, Zipp F (2010) Multiple sclerosis—candidate mechanisms underlying CNS atrophy. Trends Neurosci 33:202–210CrossRefPubMed
57.
Sorbara Catherine D, Wagner Naomi E, Ladwig A, Nikić I, Merkler D, Kleele T, Marinković P, Naumann R, Godinho L, Bareyre Florence M, Bishop D, Misgeld T, Kerschensteiner M (2014) Pervasive axonal transport deficits in multiple sclerosis models. Neuron 84:1183–1190CrossRefPubMed
58.
Takeda Y, Asou H, Murakami Y, Miura M, Kobayashi M, Uyemura K (1996) A nonneuronal isoform of cell adhesion molecule L1: tissue-specific expression and functional analysis. J Neurochem 66:2338–2349CrossRefPubMed
59.
Tanabe S, Yamashita T (2014) Repulsive guidance molecule-a is involved in Th17-cell-induced neurodegeneration in autoimmune encephalomyelitis. Cell Rep 9:1459–1470CrossRefPubMed
60.
Trapp BD, Nave KA (2008) Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 31:247–269CrossRefPubMed
61.
Tsenter J, Beni-Adani L, Assaf Y, Alexandrovich AG, Trembovler V, Shohami E (2008) Dynamic changes in the recovery after traumatic brain injury in mice: effect of injury severity on T2-weighted MRI abnormalities, and motor and cognitive functions. J Neurotrauma 25:324–333CrossRefPubMed
62.
Wehner AB, Abdesselem H, Dickendesher TL, Imai F, Yoshida Y, Giger RJ, Pierchala BA (2016) Semaphorin 3A is a retrograde cell death signal in developing sympathetic neurons. Development 143:1560–1570CrossRefPubMed
63.
Williams A, Piaton G, Aigrot M-S, Belhadi A, Théaudin M, Petermann F, Thomas J-L, Zalc B, Lubetzki C (2007) Semaphorin 3A and 3F: key players in myelin repair in multiple sclerosis? Brain 130:2554–2565CrossRefPubMed
64.
Zhao Y, Zhu M, Yu Y, Qiu L, Zhang Y, He L, Zhang J (2016) Brain REST/NRSF is not only a silent repressor but also an active protector. Mol Neurobiol 7:7
65.
Zhu Y, Romero MI, Ghosh P, Ye Z, Charnay P, Rushing EJ, Marth JD, Parada LF (2001) Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Gene Dev 15:859–876CrossRefPubMedPubMedCentral
Metadata
Title
Down-regulation of neuronal L1 cell adhesion molecule expression alleviates inflammatory neuronal injury
Authors
Lutz Menzel
Magdalena Paterka
Stefan Bittner
Robin White
Wiesia Bobkiewicz
Jack van Horssen
Melitta Schachner
Esther Witsch
Tanja Kuhlmann
Frauke Zipp
Michael K. E. Schäfer
Publication date
01-11-2016
Publisher
Springer Berlin Heidelberg
Published in
Acta Neuropathologica / Issue 5/2016
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-016-1607-4

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