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Lymphocytes reduce nigrostriatal deficits in the 6-hydroxydopamine mouse model of Parkinson’s disease

  • Translational Neurosciences - Original Article
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Abstract

Neuroinflammation is a well-known neuropathological feature of Parkinson’s disease (PD), but it remains controversial whether it is causal or consequential to neurodegeneration. While the role of microglia in the pathogenesis has been thoroughly investigated in human and different rodent models, data concerning the impact of the adaptive immune system on the pathogenesis of PD are still rare, although lymphocyte populations were found in brain tissue of PD patients and have been implicated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated neurodegeneration in mice. To test the hypothesis that the adaptive immune system contributes to the progression of PD in the murine 6-hydroxydopamine (6-OHDA) model, we performed unilateral 6-OHDA injection into the medial forebrain bundle and compared wild-type mice with recombination activating gene-1 deficient mice (RAG-1−/−), that lack mature lymphocytes. After 6-OHDA injection, immune-deficient mice moved significantly slower and less often than wild-type mice. Rotarod analysis displayed a shorter latency to fall in RAG-1−/− mice. Immunohistochemical analysis in wild-type mice demonstrated a higher CD8+ T cell density in the ipsilesional striatum compared to sham-operated animals. Cell counts of tyrosine hydroxylase positive dopaminergic neurons of the substantia nigra in immune compromised mice were significantly reduced compared to wild-type mice. Wild type bone marrow reconstitution into RAG-1−/− recipients rescued the clinical deterioration as well as the neurodegeneration in RAG-1−/− deficient recipients ameliorated clinical symptoms and neurodegeneration after 6-OHDA treatment. Our data indicate that lymphocytes reduce the clinical and neuropathological impact of 6-OHDA lesioning and thus may play a protective role in this toxic mouse model of PD.

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References

  • Anderson K, Olson K, Estes K, Flanagan K, Gendelman H, Mosley R (2014) Dual destructive and protective roles of adaptive immunity in neurodegenerative disorders. Transl Neurodegener 3(1):25

    Article  PubMed Central  PubMed  Google Scholar 

  • Baba Y, Kuroiwa A, Uitti RJ, Wszolek ZK, Yamada T (2005) Alterations of T-lymphocyte populations in Parkinson disease. Parkinsonism Relat Disord 11(8):493–498. doi:10.1016/j.parkreldis.2005.07.005

    Article  PubMed  Google Scholar 

  • Bartels AL, Leenders KL (2007) Neuroinflammation in the pathophysiology of Parkinson’s disease: evidence from animal models to human in vivo studies with [11C]-PK11195 PET. Mov Disord 22(13):1852–1856. doi:10.1002/mds.21552

    Article  PubMed  Google Scholar 

  • Bas J, Calopa M, Mestre M, Molleví DG, Cutillas B, Ambrosio S, Buendia E (2001) Lymphocyte populations in Parkinson’s disease and in rat models of parkinsonism. J Neuroimmunol 113(1):146–152. doi:10.1016/S0165-5728(00)00422-7

    Article  CAS  PubMed  Google Scholar 

  • Beahrs T, Tanzer L, Sanders VM, Jones KJ (2010) Functional recovery and facial motoneuron survival are influenced by immunodeficiency in crush-axotomized mice. Exp Neurol 221(1):225–230. doi:10.1016/j.expneurol.2009.11.003

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Boix J, Padel T, Paul G (2015) A partial lesion model of Parkinson’s disease in mice—characterization of a 6-OHDA-induced medial forebrain bundle lesion. Behav Brain Res 284:196–206. doi:10.1016/j.bbr.2015.01.053

    Article  CAS  PubMed  Google Scholar 

  • Brochard V, Combadiere B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D, Callebert J, Launay JM, Duyckaerts C, Flavell RA, Hirsch EC, Hunot S (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 119(1):182–192. doi:10.1172/JCI36470

    PubMed Central  CAS  PubMed  Google Scholar 

  • Byram SC, Carson MJ, DeBoy CA, Serpe CJ, Sanders VM, Jones KJ (2004) CD4-positive T cell-mediated neuroprotection requires dual compartment antigen presentation. J Neurosci 24(18):4333–4339

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Canh M-Y, Serpe CJ, Sanders V, Jones KJ (2006) CD4+ T cell-mediated facial motoneuron survival after injury: distribution pattern of cell death and rescue throughout the extent of the facial motor nucleus. J Neuroimmunol 181(1–2):93–99. doi:10.1016/j.jneuroim.2006.08.006

    Article  CAS  PubMed  Google Scholar 

  • Chen Z, Yu S, Concha QH, Zhu Y, Mix E, Winblad B, Ljunggren H-G, Zhu J (2004) Kainic acid-induced excitotoxic hippocampal neurodegeneration in C57BL/6 mice: B cell and T cell subsets may contribute differently to the pathogenesis. Brain Behav Immun 18(2):175–185. doi:10.1016/S0889-1591(03)00117-X

    Article  CAS  PubMed  Google Scholar 

  • Dobbs RJ, Charlett A, Purkiss AG, Dobbs SM, Weller C, Peterson DW (1999) Association of circulating TNF-alpha and IL-6 with ageing and parkinsonism. Acta Neurol Scand 100(1):34–41

    Article  CAS  PubMed  Google Scholar 

  • Gao H-M, Hong J-S (2008) Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends Immunol 29(8):357–365. doi:10.1016/j.it.2008.05.002

    Article  CAS  PubMed  Google Scholar 

  • Gao H-M, Jiang J, Wilson B, Zhang W, Hong J-S, Liu B (2002) Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson’s disease. J Neurochem 81(6):1285–1297. doi:10.1046/j.1471-4159.2002.00928.x

    Article  CAS  PubMed  Google Scholar 

  • González H, Pacheco R (2014) T-cell-mediated regulation of neuroinflammation involved in neurodegenerative diseases. J Neuroinflammation 11(1):201. doi:10.1186/s12974-014-0201-8

    Article  PubMed Central  PubMed  Google Scholar 

  • González H, Contreras F, Prado C, Elgueta D, Franz D, Bernales S, Pacheco R (2013) Dopamine receptor D3 expressed on CD4+ T cells favors neurodegeneration of dopaminergic neurons during Parkinson’s disease. J Immunol 190(10):5048–5056. doi:10.4049/jimmunol.1203121

    Article  PubMed  Google Scholar 

  • Goverman J (2009) Autoimmune T cell responses in the central nervous system. Nat Rev Immunol 9(6):393. doi:10.1038/nri2550

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Herrera AJ, Castaño A, Venero JL, Cano J, Machado A (2000) The single intranigral injection of LPS as a new model for studying the selective effects of inflammatory reactions on dopaminergic system. Neurobiol Dis 7(4):429–447. doi:10.1006/nbdi.2000.0289

    Article  CAS  PubMed  Google Scholar 

  • Herrera AJ, Tomás-Camardiel M, Venero JL, Cano J, Machado A (2005) Inflammatory process as a determinant factor for the degeneration of substantia nigra dopaminergic neurons. J Neural Transm 112(1):111–119. doi:10.1007/s00702-004-0121-3

    Article  CAS  PubMed  Google Scholar 

  • Hestvik ALK (2010) The double-edged sword of autoimmunity: lessons from multiple sclerosis. Toxins 2(4):856–877. doi:10.3390/toxins2040856

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hirsch EC, Hunot S (2009) Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol 8(4):382–397. doi:10.1016/S1474-4422(09)70062-6

    Article  CAS  PubMed  Google Scholar 

  • Hunot S, Dugas N, Faucheux B, Hartmann A, Tardieu M, Debre P, Agid Y, Dugas B, Hirsch EC (1999) FcepsilonRII/CD23 is expressed in Parkinson’s disease and induces, in vitro, production of nitric oxide and tumor necrosis factor-alpha in glial cells. J Neurosci 19(9):3440–3447

    CAS  PubMed  Google Scholar 

  • Imamura K, Hishikawa N, Sawada M, Nagatsu T, Yoshida M, Hashizume Y (2003) Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson’s disease brains. Acta Neuropathol 106(6):518–526. doi:10.1007/s00401-003-0766-2

    Article  CAS  PubMed  Google Scholar 

  • Ip C, Kroner A, Bendszus M, Leder C, Kobsar I (2006) Immune cells contribute to myelin degeneration and axonopathic changes in mice overexpressing proteolipid protein in oligodendrocytes. J Neurosci 26:8206

    Article  CAS  PubMed  Google Scholar 

  • Ip CW, Kohl B, Kleinschnitz C, Reuss B, Nave KA, Kroner A, Martini R (2008) Origin of CD11b+ macrophage-like cells in the CNS of PLP-overexpressing mice: low influx of haematogenous macrophages and unchanged blood-brain-barrier in the optic nerve. Mol Cell Neurosci 38(4):489–494

    Article  CAS  PubMed  Google Scholar 

  • Kleinschnitz C, Kraft P, Dreykluft A, Hagedorn I, Göbel K, Schuhmann MK, Langhauser F, Helluy X, Schwarz T, Bittner S, Mayer CT, Brede M, Varallyay C, Pham M, Bendszus M, Jakob P, Magnus T, Meuth SG, Iwakura Y, Zernecke A, Sparwasser T, Nieswandt B, Stoll G, Wiendl H (2013) Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature. Blood 121(4):679–691. doi:10.1182/blood-2012-04-426734

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Knott C, Stern G, Wilkin GP (2000) Inflammatory Regulators in Parkinson’s Disease: iNOS, Lipocortin-1, and Cyclooxygenases-1 and -2. Mol Cell Neurosci 16(6):724–739. doi:10.1006/mcne.2000.0914

    Article  CAS  PubMed  Google Scholar 

  • Kupsch A, Schmidt W, Gizatullina Z, Debska-Vielhaber G, Voges J, Striggow F, Panther P, Schwegler H, Heinze H-J, Vielhaber S, Gellerich F (2014) 6-Hydroxydopamine impairs mitochondrial function in the rat model of Parkinson’s disease: respirometric, histological, and behavioral analyses. J Neural Transm 121(10):1245–1257. doi:10.1007/s00702-014-1185-3

    Article  CAS  PubMed  Google Scholar 

  • Marinova-Mutafchieva L, Sadeghian M, Broom L, Davis JB, Medhurst AD, Dexter DT (2009) Relationship between microglial activation and dopaminergic neuronal loss in the substantia nigra: a time course study in a 6-hydroxydopamine model of Parkinson’s disease. J Neurochem 110(3):966–975. doi:10.1111/j.1471-4159.2009.06189.x

    Article  CAS  PubMed  Google Scholar 

  • McGeer PL, Itagaki S, Akiyama H, McGeer EG (1988a) Rate of cell death in parkinsonism indicates active neuropathological process. Ann Neurol 24(4):574–576. doi:10.1002/ana.410240415

    Article  CAS  PubMed  Google Scholar 

  • McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988b) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38(8):1285–1291

    Article  CAS  PubMed  Google Scholar 

  • Miller A, Lider O, Roberts AB, Sporn MB, Weiner HL (1992) Suppressor T cells generated by oral tolerization to myelin basic protein suppress both in vitro and in vivo immune responses by the release of transforming growth factor beta after antigen-specific triggering. Proc Natl Acad Sci USA 89(1):421–425

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mogi M, Harada M, Kondo T, Riederer P, Inagaki H, Minami M, Nagatsu T (1994a) Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients. Neurosci Lett 180(2):147–150

    Article  CAS  PubMed  Google Scholar 

  • Mogi M, Harada M, Riederer P, Narabayashi H, Fujita K, Nagatsu T (1994b) Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci Lett 165(1–2):208–210

    Article  CAS  PubMed  Google Scholar 

  • Mogi M, Harada M, Kondo T, Narabayashi H, Riederer P, Nagatsu T (1995) Transforming growth factor-beta 1 levels are elevated in the striatum and in ventricular cerebrospinal fluid in Parkinson’s disease. Neurosci Lett 193(2):129–132

    Article  CAS  PubMed  Google Scholar 

  • Mogi M, Harada M, Kondo T, Riederer P, Nagatsu T (1996) Interleukin-2 but not basic fibroblast growth factor is elevated in parkinsonian brain. Short communication. J Neural Transm 103(8–9):1077–1081

    Article  CAS  PubMed  Google Scholar 

  • Polazzi E, Altamira LEP, Eleuteri S, Barbaro R, Casadio C, Contestabile A, Monti B (2009) Neuroprotection of microglial conditioned medium on 6-hydroxydopamine-induced neuronal death: role of transforming growth factor beta-2. J Neurochem 110(2):545–556. doi:10.1111/j.1471-4159.2009.06117.x

    Article  CAS  PubMed  Google Scholar 

  • Qian L, Flood P, Hong J-S (2010) Neuroinflammation is a key player in Parkinson’s disease and a prime target for therapy. J Neural Transm 117(8):971–979. doi:10.1007/s00702-010-0428-1

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Reynolds AD, Stone DK, Mosley RL, Gendelman HE (2009) Proteomic Studies of Nitrated Alpha-Synuclein Microglia Regulation by CD4+ CD25+ T Cells. J Proteome Res 8(7):3497–3511. doi:10.1021/pr9001614

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rosenkranz D, Weyer S, Tolosa E, Gaenslen A, Berg D, Leyhe T, Gasser T, Stoltze L (2007) Higher frequency of regulatory T cells in the elderly and increased suppressive activity in neurodegeneration. J Neuroimmunol 188(1–2):117–127. doi:10.1016/j.jneuroim.2007.05.011

    Article  CAS  PubMed  Google Scholar 

  • Schapira AHV (2004) Disease modification in Parkinson’s disease. Lancet Neurol 3(6):362–368. doi:10.1016/S1474-4422(04)00769-0

    Article  CAS  PubMed  Google Scholar 

  • Serpe CJ, Kohm AP, Huppenbauer CB, Sanders VM, Jones KJ (1999) Exacerbation of facial motoneuron loss after facial nerve transection in severe combined immunodeficient (scid) mice. J Neurosci 19(11):RC7

    CAS  PubMed  Google Scholar 

  • Serpe CJ, Sanders VM, Jones KJ (2000) Kinetics of facial motoneuron loss following facial nerve transection in severe combined immunodeficient mice. J Neurosci Res 62(2):273–278. doi:10.1002/1097-4547(20001015)62:2<273:AID-JNR11>3.0.CO;2-C

    Article  CAS  PubMed  Google Scholar 

  • Serpe CJ, Coers S, Sanders VM, Jones KJ (2003) CD4+ T, but not CD8+ or B, lymphocytes mediate facial motoneuron survival after facial nerve transection. Brain Behav Immun 17(5):393–402. doi:10.1016/S0889-1591(03)00028-X

    Article  PubMed  Google Scholar 

  • Stypula G, Kunert-Radek J, Stepien H, Zylinska K, Pawlikowski M (1996) Evaluation of interleukins, ACTH, cortisol and prolactin concentrations in the blood of patients with Parkinson’s disease. Neuroimmunomodulation 3(2–3):131–134

    CAS  PubMed  Google Scholar 

  • Thiele SL, Warre R, Nash JE (2012) Development of a unilaterally-lesioned 6-OHDA mouse model of Parkinson’s disease. J Vis Exp 60:3234. doi:10.3791/3234

    PubMed  Google Scholar 

  • Wheeler CJ, Seksenyan A, Koronyo Y, Rentsendorj A, Sarayba D, Wu H, Gragg A, Siegel E, Thomas D, Espinosa A, Thompson K, Black K, Koronyo-Hamaoui M, Pechnick R, Irvin DK (2014) T-Lymphocyte Deficiency Exacerbates Behavioral Deficits in the 6-OHDA Unilateral Lesion Rat Model for Parkinson’s Disease. J Neurol Neurophysiol. doi:10.4172/2155-9562.1000209

    PubMed Central  PubMed  Google Scholar 

  • Wilms H, Zecca L, Rosenstiel P, Sievers J, Deuschl G, Lucius R (2007) Inflammation in Parkinson’s diseases and other neurodegenerative diseases: cause and therapeutic implications. Curr Pharm Des 13(18):1925–1928

    Article  CAS  PubMed  Google Scholar 

  • Wyss-Coray T, Mucke L (2002) Inflammation in neurodegenerative disease–a double-edged sword. Neuron 35(3):419–432

    Article  CAS  PubMed  Google Scholar 

  • Yanamandra K, Gruden MA, Casaite V, Meskys R, Forsgren L, Morozova-Roche LA (2011) α-synuclein reactive antibodies as diagnostic biomarkers in blood sera of Parkinson’s disease patients. PLoS One 6(4):e18513. doi:10.1371/journal.pone.0018513

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zigmond MJ, Hastings TG, Abercrombie ED (1992) Neurochemical responses to 6-hydroxydopamine and L-dopa therapy: implications for Parkinson’s disease. Ann N Y Acad Sci 648:71–86

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are grateful to Heinrich Blazyca, Silke Loserth and Bettina Meyer for their expert technical assistance, to Helga Brünner for the animal care and to Professor Rudolf Martini for discussions. The work was supported by the State of Bavaria.

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  1. Department of Neurology, University of Wuerzburg, Josef-Schneider-Strasse 11, 97080, Würzburg, Germany

    Chi Wang Ip, Sandra K. Beck & Jens Volkmann

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  1. Chi Wang Ip
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  2. Sandra K. Beck
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Correspondence to Chi Wang Ip.

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CW.I. Has served on scientific boards for Merz Pharmaceuticals, LLC and TEVA; has received funding for travel from Ipsen, Merz Pharmaceuticals, LLC, and Allergan, Inc.; has received speaker honoraria from Merz, TEVA, Allergan, Inc. J.V. Has served as a consultant for Medtronic, GlaxoSmithKline, and Abbott and has received honoraria from Medtronic, GlaxoSmithKline, Abbott, Boehringer, TEVA, UCB, and Orion.

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Ip, C.W., Beck, S.K. & Volkmann, J. Lymphocytes reduce nigrostriatal deficits in the 6-hydroxydopamine mouse model of Parkinson’s disease. J Neural Transm 122, 1633–1643 (2015). https://doi.org/10.1007/s00702-015-1444-y

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