Molecular Neurobiology

, Volume 54, Issue 10, pp 7762–7776 | Cite as

Th17 Cells Induce Dopaminergic Neuronal Death via LFA-1/ICAM-1 Interaction in a Mouse Model of Parkinson’s Disease

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Abstract

T helper (Th)17 cells, a subset of CD4+ T lymphocytes, have strong pro-inflammatory property and appear to be essential in the pathogenesis of many inflammatory diseases. However, the involvement of Th17 cells in Parkinson’s disease (PD) that is characterized by a progressive degeneration of dopaminergic (DAergic) neurons in the nigrostriatal system is unclear. Here, we aimed to demonstrate that Th17 cells infiltrate into the brain parenchyma and induce neuroinflammation and DAergic neuronal death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- or 1-methyl-4-phenylpyridinium (MPP+)-induced PD models. Blood–brain barrier (BBB) disruption in the substantia nigra (SN) was assessed by the signal of FITC-labeled albumin that was injected into blood circulation via the ascending aorta. Live cell imaging system was used to observe a direct contact of Th17 cells with neurons by staining these cells using the two adhesion molecules, leukocyte function-associated antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-1, respectively. Th17 cells invaded into the SN where BBB was disrupted in MPTP-induced PD mice. Th17 cells exacerbated DAergic neuronal loss and pro-inflammatory/neurotrophic factor disorders in MPP+-treated ventral mesencephalic (VM) cell cultures. A direct contact of LFA-1-stained Th17 cells with ICAM-1-stained VM neurons was dynamically captured. Either blocking LFA-1 in Th17 cells or blocking ICAM-1 in VM neurons with neutralizing antibodies abolished Th17-induced DAergic neuronal death. These results establish that Th17 cells infiltrate into the brain parenchyma of PD mice through lesioned BBB and exert neurotoxic property by promoting glial activation and importantly by a direct damage to neurons depending on LFA-1/ICAM-1 interaction.

Keywords

Th17 cells Parkinson’s disease Neuroinflammation LFA-1 ICAM-1 
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Notes

Acknowledgements

This work was supported by grants 81271323 and 31371182 from the National Natural Science Foundation of China, MS12015104 and MS12015096 from the Nantong Applied Research Program of China, and a project funded by the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.

Compliance with Ethical Standards

All animal procedures were in accordance with the National Institutes of Health guidelines and were approved by the Institutional Animal Care and Use Committee of Nantong University.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2016_249_MOESM1_ESM.mp4 (153 kb)
ESM 1 (MP4 152 kb)

References

  1. 1.
    Qian L, Flood PM, Hong JS (2010) Neuroinflammation is a key player in Parkinson’s disease and a prime target for therapy. J Neural Transm 117:971–979CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Brochard V, Combadière B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D et al (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 119:182–192PubMedGoogle Scholar
  3. 3.
    Benner EJ, Banerjee R, Reynolds AD, Sherman S, Pisarev VM, Tsiperson V, Nemachek C, Ciborowski P et al (2008) Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One 3:e1376CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Korn T, Bettelli E, Gao W, Awasthi A, Jäger A, Strom TB, Oukka M, Kuchroo VK (2007) IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448:484–487CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Miossec P, Korn T, Kuchroo VK (2009) Interleukin-17 and type 17 helper T cells. N Engl J Med 361:888–898CrossRefPubMedGoogle Scholar
  6. 6.
    Noack M, Miossec P (2014) Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev 13:668–677CrossRefPubMedGoogle Scholar
  7. 7.
    Gao HM, Liu B, Hong JS (2003) Critical role for microglial NADPH oxidase in rotenone-induced degeneration of dopaminergic neurons. J Neurosci 23:6181–6187PubMedGoogle Scholar
  8. 8.
    Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69CrossRefPubMedGoogle Scholar
  9. 9.
    Zimmermann J, Krauthausen M, Hofer MJ, Heneka MT, Campbell IL, Müller M (2013) CNS-targeted production of IL-17A induces glial activation, microvascular pathology and enhances the neuroinflammatory response to systemic endotoxemia. PLoS One 8:e57307CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Waisman A, Hauptmann J, Regen T (2015) The role of IL-17 in CNS diseases. Acta Neuropathol 129:625–637CrossRefPubMedGoogle Scholar
  11. 11.
    Whitton PS (2007) Inflammation as a causative factor in the aetiology of Parkinson’s disease. Br J Pharmacol 150:963–976CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Amor S, Puentes F, Baker D, van der Valk P (2010) Inflammation in neurodegenerative diseases. Immunology 129:154–169CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Appel SH, Beers DR, Henkel JS (2010) T cell-microglial dialogue in Parkinson’s disease and amyotrophic lateral sclerosis: are we listening? Trends Immunol 31:7–17CrossRefPubMedGoogle Scholar
  14. 14.
    Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Liu RP, Zou M, Wang JY, Zhu JJ, Lai JM, Zhou LL, Chen SF, Zhang X et al (2014) Paroxetine ameliorates lipopolysaccharide-induced microglia activation via differential regulation of MAPK signaling. J Neuroinflammation 11:47CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Russo I, Bubacco L, Greggio E (2014) LRRK2 and neuroinflammation: partners in crime in Parkinson’s disease? J Neuroinflammation 11:52CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kawanokuchi J, Shimizu K, Nitta A, Yamada K, Mizuno T, Takeuchi H, Suzumura A (2008) Production and functions of IL-17 in microglia. J Neuroimmunol 194:54–61CrossRefPubMedGoogle Scholar
  18. 18.
    Semmrich M, Smith A, Feterowski C, Beer S, Engelhardt B, Busch DH, Bartsch B, Laschinger M et al (2005) Importance of integrin LFA-1 deactivation for the generation of immune responses. J Exp Med 201:1987–1998CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hogg N, Laschinger M, Giles K, McDowall A (2003) T-cell integrins: more than just sticking points. J Cell Sci 116:4695–4705CrossRefPubMedGoogle Scholar
  20. 20.
    Anikeeva N, Somersalo K, Sims TN, Thomas VK, Dustin ML, Sykulev Y (2005) Distinct role of lymphocyte function-associated antigen-1 in mediating effective cytolytic activity by cytotoxic T lymphocytes. Proc Natl Acad Sci U S A 102:6437–6442CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Jing L, Wang JG, Zhang JZ, Cao CX, Chang Y, Dong JD, Guo FY, Li PA (2014) Upregulation of ICAM-1 in diabetic rats after transient forebrain ischemia and reperfusion injury. J Inflamm (Lond) 11:35CrossRefGoogle Scholar
  22. 22.
    Bianchi E, Denti S, Granata A, Bossi G, Geginat J, Villa A, Rogge L, Pardi R (2000) Integrin LFA-1 interacts with the transcriptional coactivator JAB1 to modulate AP-1 activity. Nature 404:617–621CrossRefPubMedGoogle Scholar
  23. 23.
    Perez OD, Mitchell D, Jager GC, South S, Murriel C, McBride J, Herzenberg LA, Kinoshita S et al (2003) Leukocyte functional antigen 1 lowers T cell activation thresholds and signaling through cytohesin-1 and Jun-activating binding protein 1. Nat Immunol 4:1083–1092CrossRefPubMedGoogle Scholar
  24. 24.
    Shimizu Y (2003) LFA-1: more than just T cell velcro. Nat Immunol 4:1052–1054CrossRefPubMedGoogle Scholar
  25. 25.
    Przedborski S, Jackson-Lewis V, Naini AB, Jakowec M, Petzinger G, Miller R, Akram M (2001) The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP): a technical review of its utility and safety. J Neurochem 76:1265–1274CrossRefPubMedGoogle Scholar
  26. 26.
    Marchi N, Guiso G, Caccia S, Rizzi M, Gagliardi B, Noé F, Ravizza T, Bassanini S et al (2006) Determinants of drug brain uptake in a rat model of seizure-associated malformations of cortical development. Neurobiol Dis 24:429–442CrossRefPubMedGoogle Scholar
  27. 27.
    Gao HM, Kotzbauer PT, Uryu K, Leight S, Trojanowski JQ, Lee VM (2008) Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration. J Neurosci 28:7687–7698CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Franklin KBJ, Paxinos G (2007) The mouse brain in stereotaxic coordinates, Third edn. Academic Press, Elsevier, New YorkGoogle Scholar
  29. 29.
    Giuliani F, Goodyer CG, Antel JP, Yong VW (2003) Vulnerability of human neurons to T cell-mediated cytotoxicity. J Immunol 171:368–379CrossRefPubMedGoogle Scholar
  30. 30.
    Duman RS, Terwilliger RZ, Nestler EJ, Tallman JF (1989) Sodium and potassium regulation of guanine nucleotide-stimulated adenylate cyclase in brain. Biochem Pharmacol 38:1909–1914CrossRefPubMedGoogle Scholar
  31. 31.
    Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909CrossRefPubMedGoogle Scholar
  32. 32.
    Miklossy J, Doudet DD, Schwab C, Yu S, McGeer EG, McGeer PL (2006) Role of ICAM-1 in persisting inflammation in Parkinson disease and MPTP monkeys. Exp Neurol 197:275–283CrossRefPubMedGoogle Scholar
  33. 33.
    Zhang J, Ke KF, Liu Z, Qiu YH, Peng YP (2013) Th17 cell-mediated neuroinflammation is involved in neurodegeneration of aβ1-42-induced Alzheimer’s disease model rats. PLoS One 8:e75786CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, Giuliani F, Arbour N et al (2007) Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med 13:1173–1175CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Kang Z, Altuntas CZ, Gulen MF, Liu C, Giltiay N, Qin H, Liu L, Qian W et al (2010) Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity 32:414–425CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Verreck FA, de Boer T, Langenberg DM, Hoeve MA, Kramer M, Vaisberg E, Kastelein R, Kolk A et al (2004) Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco) bacteria. Proc Natl Acad Sci U S A 101:4560–4565CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W et al (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421:744–748CrossRefPubMedGoogle Scholar
  38. 38.
    Kang Z, Wang C, Zepp J, Wu L, Sun K, Zhao J, Chandrasekharan U, DiCorleto PE et al (2013) Act1 mediates IL-17-induced EAE pathogenesis selectively in NG2+ glial cells. Nat Neurosci 16:1401–1408CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Zhu Y, Chen X, Liu Z, Peng YP, Qiu YH (2015) Interleukin-10 protection against lipopolysaccharide-induced neuro-inflammation and neurotoxicity in ventral mesencephalic cultures. Int J Mol Sci 17. doi: 10.3390/ijms17010025
  40. 40.
    Lim SW, Shiue YL, Liao JC, Wee HY, Wang CC, Chio CC, Chang CH, Hu CY et al (2016) Simvastatin therapy in the acute stage of traumatic brain injury attenuates brain trauma-induced depression-like behavior in rats by reducing neuroinflammation in the hippocampus. Neurocrit Care. doi: 10.1007/s12028-016-0290-6 Google Scholar
  41. 41.
    Carta AR, Frau L, Pisanu A, Wardas J, Spiga S, Carboni E (2011) Rosiglitazone decreases peroxisome proliferator receptor-γ levels in microglia and inhibits TNF-α production: new evidences on neuroprotection in a progressive Parkinson’s disease model. Neuroscience 194:250–261CrossRefPubMedGoogle Scholar
  42. 42.
    Reynolds AD, Stone DK, Mosley RL, Gendelman HE (2009) Nitrated {alpha}-synuclein-induced alterations in microglial immunity are regulated by CD4+ T cell subsets. J Immunol 182:4137–4149CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Siffrin V, Radbruch H, Glumm R, Niesner R, Paterka M, Herz J, Leuenberger T, Lehmann SM et al (2010) In vivo imaging of partially reversible Th17 cell-induced neuronal dysfunction in the course of encephalomyelitis. Immunity 33:424–436CrossRefPubMedGoogle Scholar
  44. 44.
    Huse M, Quann EJ, Davis MM (2008) Shouts, whispers and the kiss of death: directional secretion in T cells. Nat Immunol 9:1105–1111CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Nijboer CH, van der Kooij MA, van Bel F, Ohl F, Heijnen CJ, Kavelaars A (2010) Inhibition of the JNK/AP-1 pathway reduces neuronal death and improves behavioral outcome after neonatal hypoxic-ischemic brain injury. Brain Behav Immun 24:812–821CrossRefPubMedGoogle Scholar
  46. 46.
    Saporito MS, Thomas BA, Scott RW (2000) MPTP activates c-Jun NH(2)-terminal kinase (JNK) and its upstream regulatory kinase MKK4 in nigrostriatal neurons in vivo. J Neurochem 75:1200–1208CrossRefPubMedGoogle Scholar
  47. 47.
    Xia XG, Harding T, Weller M, Bieneman A, Uney JB, Schulz JB (2001) Gene transfer of the JNK interacting protein-1 protects dopaminergic neurons in the MPTP model of Parkinson’s disease. Proc Natl Acad Sci U S A 98:10433–10438CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Physiology, School of Medicine, and Co-innovation Center of NeuroregenerationNantong UniversityNantongChina

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