Table of Contents Author Guidelines Submit a Manuscript
BioMed Research International
Volume 2014, Article ID 308654, 9 pages
http://dx.doi.org/10.1155/2014/308654
Review Article

Evidence of Inflammatory System Involvement in Parkinson’s Disease

1National Neuroscience Institute, Singapore 308433
2Duke-National University of Singapore Graduate Medical School, Singapore 169857
3Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648
4Department of Microbiology, National University of Singapore, Singapore 117545
5Department of Neurology, Singapore General Hospital, Singapore 169608
6Department of Neurology, National Neuroscience Institute (SGH Campus), 20 College Road, Academia Level 4, Singapore 169856

Received 11 April 2014; Revised 30 May 2014; Accepted 30 May 2014; Published 24 June 2014

Academic Editor: Amit K. Srivastava

Copyright © 2014 Yinxia Chao et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. W. Dauer and S. Przedborski, “Parkinson's disease: mechanisms and models,” Neuron, vol. 39, no. 6, pp. 889–909, 2003. View at Publisher · View at Google Scholar · View at Scopus
  2. A. Członkowska, I. Kurkowska-Jastrzebska, A. Członkowski, D. Peter, and G. B. Stefano, “Immune processes in the pathogenesis of Parkinson's disease—a potential role for microglia and nitric oxide,” Medical Science Monitor, vol. 8, no. 8, pp. RA165–RA177, 2002. View at Google Scholar
  3. P. S. Whitton, “Inflammation as a causative factor in the aetiology of Parkinson's disease,” British Journal of Pharmacology, vol. 150, no. 8, pp. 963–976, 2007. View at Publisher · View at Google Scholar · View at Scopus
  4. D. K. Kim, H. S. Kim, A. Kim et al., “DJ-1 regulates mast cell activation and IgE-mediated allergic responses,” Journal of Allergy and Clinical Immunology, vol. 131, no. 6, pp. 1653–1662, 2013. View at Publisher · View at Google Scholar · View at Scopus
  5. P. S. Manzanillo, J. S. Ayres, R. O. Watson et al., “The ubiquitin ligase parkin mediates resistance to intracellular pathogens,” Nature, vol. 501, no. 7468, pp. 512–516, 2013. View at Publisher · View at Google Scholar · View at Scopus
  6. M. Deleidi, P. J. Hallett, J. B. Koprich, C. Chung, and O. Isacson, “The toll-like receptor-3 agonist polyinosinic:polycytidylic acid triggers nigrostriatal dopaminergic degeneration,” Journal of Neuroscience, vol. 30, no. 48, pp. 16091–16101, 2010. View at Publisher · View at Google Scholar · View at Scopus
  7. L. Qin, Y. Liu, J. Hong, and F. T. Crews, “NADPH oxidase and aging drive microglial activation, oxidative stress, and dopaminergic neurodegeneration following systemic LPS administration,” GLIA, vol. 61, no. 6, pp. 855–868, 2013. View at Publisher · View at Google Scholar · View at Scopus
  8. K. Tanji, F. Mori, T. Imaizumi et al., “Upregulation of α-synuclein by lipopolysaccharide and interleukin-1 in human macrophages,” Pathology International, vol. 52, no. 9, pp. 572–577, 2002. View at Publisher · View at Google Scholar · View at Scopus
  9. I. Russo, L. Bubacco, and E. Greggio, “LRRK2 and neuroinflammation: partners in crime in Parkinson's disease?” Journal of Neuroinflammation, vol. 11, article 52, 2014. View at Publisher · View at Google Scholar
  10. B. Brodacki, J. Staszewski, B. Toczyłowska et al., “Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFα, and INFγ concentrations are elevated in patients with atypical and idiopathic parkinsonism,” Neuroscience Letters, vol. 441, no. 2, pp. 158–162, 2008. View at Publisher · View at Google Scholar · View at Scopus
  11. M. Reale, N. H. Greig, and M. A. Kamal, “Peripheral chemo-cytokine profiles in Alzheimer's and Parkinson's diseases,” Mini-Reviews in Medicinal Chemistry, vol. 9, no. 10, pp. 1229–1241, 2009. View at Publisher · View at Google Scholar · View at Scopus
  12. I. U. Song, J. S. Kim, S. W. Chung, and K. S. Lee, “Is there an association between the level of high-sensitivity C-reactive protein and idiopathic parkinson's disease? A comparison of parkinson's disease patients, disease controls and healthy individuals,” European Neurology, vol. 62, no. 2, pp. 99–104, 2009. View at Publisher · View at Google Scholar · View at Scopus
  13. M. Mogi, M. Harada, T. Kondob et al., “Interleukin-1β, interleukin-6, epidermal growth factor and transforming growth factor-α are elevated in the brain from parkinsonian patients,” Neuroscience Letters, vol. 180, no. 2, pp. 147–150, 1994. View at Publisher · View at Google Scholar · View at Scopus
  14. M. Mogi, M. Harada, T. Kondo, P. Riederer, and T. Nagatsu, “Brain β2-microglobulin levels are elevated in the striatum in Parkinson's diseaselevels are elevated in the striatum in Parkinson's disease,” Journal of Neural Transmission: Parkinson's Disease and Dementia Section, vol. 9, no. 1, pp. 87–92, 1995. View at Publisher · View at Google Scholar · View at Scopus
  15. D. Blum-Degen, T. Müller, and W. Kuhn, “Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients,” Neuroscience Letters, vol. 202, pp. 17–20, 1995. View at Publisher · View at Google Scholar
  16. M. P. Mount, A. Lira, D. Grimes et al., “Involvement of interferon-γ in microglial-mediated loss of dopaminergic neurons,” Journal of Neuroscience, vol. 27, no. 12, pp. 3328–3337, 2007. View at Publisher · View at Google Scholar · View at Scopus
  17. E. Kim and O. Hwang, “Role of matrix metalloproteinase-3 in neurodegeneration,” Journal of Neurochemistry, vol. 116, no. 1, pp. 22–32, 2011. View at Publisher · View at Google Scholar · View at Scopus
  18. Y. C. Chung, Y. Kim, E. Bok, T. Y. Yune, S. Maeng, and B. K. Jin, “MMP-3 contributes to nigrostriatal dopaminergic neuronal loss, BBB damage, and neuroinflammation in an MPTP mouse model of Parkinson's disease,” Mediators of Inflammation, vol. 2013, Article ID 370526, 11 pages, 2013. View at Publisher · View at Google Scholar · View at Scopus
  19. S. Yamada, T. Nagai, T. Nakai et al., “Matrix metalloproteinase-3 is a possible mediator of neurodevelopmental impairment due to polyI: C-induced innate immune activation of astrocytes,” Brain, Behavior, and Immunity, vol. 38, pp. 272–282, 2014. View at Publisher · View at Google Scholar
  20. C. T. Fagundes, V. V. Costa, D. Cisalpino et al., “IFN-γ production depends on IL-12 and IL-18 combined action and mediates host resistance to dengue virus infection in a nitric oxide-dependent manner,” PLoS Neglected Tropical Diseases, vol. 5, no. 12, article e1449, 2011. View at Publisher · View at Google Scholar · View at Scopus
  21. Y. Kannan, J. Yu, R. M. Raices et al., “IκBζ augments IL-12- and IL-18-mediated IFN-γ production in human NK cells,” Blood, vol. 117, no. 10, pp. 2855–2863, 2011. View at Publisher · View at Google Scholar · View at Scopus
  22. H. K. Takahashi, H. Iwagaki, R. Hamano et al., “Effects of adenosine on adhesion molecule expression and cytokine production in human PBMC depend on the receptor subtype activated,” British Journal of Pharmacology, vol. 150, no. 6, pp. 816–822, 2007. View at Publisher · View at Google Scholar · View at Scopus
  23. A. Gillett, M. T. Hedreul, M. Khademi et al., “Interleukin 18 receptor 1 expression distinguishes patients with multiple sclerosis,” Multiple Sclerosis, vol. 16, no. 9, pp. 1056–1065, 2010. View at Publisher · View at Google Scholar · View at Scopus
  24. J. M. Millward, M. Løbner, R. D. Wheeler, and T. Owens, “Inflammation in the central nervous system and Th17 responses are inhibited by IFN-γ-induced IL-18 binding protein,” The Journal of Immunology, vol. 185, no. 4, pp. 2458–2466, 2010. View at Publisher · View at Google Scholar · View at Scopus
  25. S. K. Celik, Z. S. Öz, A. Dursun et al., “Interleukin 18 gene polymorphism is a risk factor for multiple sclerosis,” Molecular Biology Reports, vol. 41, no. 3, pp. 1653–1658, 2014. View at Publisher · View at Google Scholar
  26. S. Sugama, S. A. Wirz, A. M. Barr, B. Conti, T. Bartfai, and T. Shibasaki, “Interleukin-18 null mice show diminished microglial activation and reduced dopaminergic neuron loss following acute 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine treatment,” Neuroscience, vol. 128, no. 2, pp. 451–458, 2004. View at Publisher · View at Google Scholar · View at Scopus
  27. X. Xu, D. Li, Q. He, J. Gao, B. Chen, and A. Xie, “Interleukin-18 promoter polymorphisms and risk of Parkinson's disease in a Han Chinese population,” Brain Research, vol. 1381, pp. 90–94, 2011. View at Publisher · View at Google Scholar · View at Scopus
  28. K. Nie, Y. Zhang, R. Gan et al., “Polymorphisms in immune/inflammatory cytokine genes are related to Parkinson's disease with cognitive impairment in the Han Chinese population,” Neuroscience Letters, vol. 541, pp. 111–115, 2013. View at Publisher · View at Google Scholar · View at Scopus
  29. T. Yamada, P. L. McGeer, and E. G. McGeer, “Lewy bodies in Parkinson's disease are recognized by antibodies to complement proteins,” Acta Neuropathologica, vol. 84, no. 1, pp. 100–104, 1992. View at Publisher · View at Google Scholar · View at Scopus
  30. D. Koziorowski, R. Tomasiuk, S. Szlufik, and A. Friedman, “Inflammatory cytokines and NT-proCNP in Parkinson's disease patients,” Cytokine, vol. 60, no. 3, pp. 762–766, 2012. View at Publisher · View at Google Scholar · View at Scopus
  31. D. Béraud, H. A. Hathaway, J. Trecki et al., “Microglial activation and antioxidant responses induced by the Parkinson's disease protein α-synuclein,” Journal of Neuroimmune Pharmacology, vol. 8, no. 1, pp. 94–117, 2013. View at Publisher · View at Google Scholar · View at Scopus
  32. C. Iwamura and T. Nakayama, “Toll-like receptors in the respiratory system: their roles in inflammation,” Current Allergy and Asthma Reports, vol. 8, no. 1, pp. 7–13, 2008. View at Publisher · View at Google Scholar · View at Scopus
  33. E. Cario, “Toll-like receptors in inflammatory bowel diseases: a decade later,” Inflammatory Bowel Diseases, vol. 16, no. 9, pp. 1583–1597, 2010. View at Publisher · View at Google Scholar · View at Scopus
  34. A. N. Seneviratne, B. Sivagurunathan, and C. Monaco, “Toll-like receptors and macrophage activation in atherosclerosis,” Clinica Chimica Acta, vol. 413, no. 1-2, pp. 3–14, 2012. View at Publisher · View at Google Scholar · View at Scopus
  35. T. Brudek, K. Winge, T. K. Agander, and B. Pakkenberg, “Screening of toll-like receptors expression in multiple system atrophy brains,” Neurochemical Research, vol. 38, no. 6, pp. 1252–1259, 2013. View at Publisher · View at Google Scholar · View at Scopus
  36. C. Roodveldt, A. Labrador-Garrido, E. Gonzalez-Rey et al., “Preconditioning of microglia by α-synuclein strongly affects the response induced by toll-like receptor (TLR) stimulation,” PLoS ONE, vol. 8, no. 11, Article ID e79160, 2013. View at Google Scholar
  37. M. Saresella, I. Marventano, E. Calabrese et al., “A complex proinflammatory role for peripheral monocytes in Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 403–413, 2014. View at Publisher · View at Google Scholar
  38. I. Hafner-Bratkovič, M. Benčina, K. A. Fitzgerald, D. Golenbock, and R. Jerala, “NLRP3 inflammasome activation in macrophage cell lines by prion protein fibrils as the source of IL-1β and neuronal toxicity,” Cellular and Molecular Life Sciences, vol. 69, no. 24, pp. 4215–4228, 2012. View at Publisher · View at Google Scholar · View at Scopus
  39. M. Schnaars, H. Beckert, and A. Halle, “Assessing β-amyloid-induced NLRP3 inflammasome activation in primary microglia,” Methods in Molecular Biology, vol. 1040, pp. 1–8, 2013. View at Publisher · View at Google Scholar · View at Scopus
  40. M. Tan, J. Yu, T. Jiang, X. Zhu, and L. Tan, “The NLRP3 inflammasome in Alzheimer's disease,” Molecular Neurobiology, vol. 48, no. 3, pp. 875–882, 2013. View at Publisher · View at Google Scholar · View at Scopus
  41. X. F. Meng, X. L. Wang, X. J. Tian et al., “Nod-like receptor protein 1 inflammasome mediates neuron injury under high glucose,” Molecular Neurobiology, vol. 49, no. 2, pp. 673–684, 2014. View at Google Scholar
  42. M. J. Devine, A. Kaganovich, M. Ryten et al., “Pathogenic LRRK2 mutations do not alter gene expression in cell model systems or human brain tissue,” PLoS ONE, vol. 6, no. 7, Article ID e22489, 2011. View at Publisher · View at Google Scholar · View at Scopus
  43. A. Ohta and M. Sitkovsky, “Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage,” Nature, vol. 414, no. 6866, pp. 916–920, 2001. View at Publisher · View at Google Scholar · View at Scopus
  44. N. Saha, F. Moldovan, G. Tardif et al., “Interleukin-1β-converting enzyme (caspase-1) in human osteoarthritic tissues. Localization and role in the maturation of interleukin-1β and interleukin-18,” Arthritis & Rheumatism, vol. 42, no. 8, pp. 1577–1587, 1999. View at Google Scholar
  45. G. W. Sullivan, “Adenosine A2A receptor agonists as anti-inflammatory agents,” Current Opinion in Investigational Drugs, vol. 4, no. 11, pp. 1313–1319, 2003. View at Google Scholar · View at Scopus
  46. T. Yamagata and M. Ichinose, “Agents against cytokine synthesis or receptors,” European Journal of Pharmacology, vol. 533, no. 1–3, pp. 289–301, 2006. View at Publisher · View at Google Scholar · View at Scopus
  47. F. Vincenzi, C. Corciulo, M. Targa et al., “Multiple sclerosis lymphocytes upregulate A2A adenosine receptors that are antiinflammatory when stimulated,” European Journal of Immunology, vol. 43, no. 8, pp. 2206–2216, 2013. View at Publisher · View at Google Scholar · View at Scopus
  48. G. Burnstock, B. B. Fredholm, and A. Verkhratsky, “Adenosine and ATP receptors in the brain,” Current Topics in Medicinal Chemistry, vol. 11, no. 8, pp. 973–1011, 2011. View at Publisher · View at Google Scholar · View at Scopus
  49. I. Casetta, F. Vincenzi, D. Bencivelli et al., “A2A adenosine receptors and Parkinson's disease severity,” Acta Neurologica Scandinavica, vol. 129, no. 4, pp. 276–281, 2014. View at Publisher · View at Google Scholar · View at Scopus
  50. S. Khanapur, A. V. Waarde, K. Ishiwata et al., “Adenosine A2A receptor Antagonists as Positron Emission Tomography (PET) Tracers,” Current Medicinal Chemistry, vol. 21, no. 3, pp. 312–328, 2013. View at Google Scholar
  51. S. H. Fox, “Non-dopaminergic treatments for motor control in Parkinson's disease,” Drugs, vol. 73, no. 13, pp. 1405–1415, 2013. View at Publisher · View at Google Scholar
  52. Y. X. Chao, B. P. He, and S. S. Tay, “Mesenchymal stem cell transplantation attenuates blood brain barrier damage and neuroinflammation and protects dopaminergic neurons against MPTP toxicity in the substantia nigra in a model of Parkinson's disease,” Journal of Neuroimmunology, vol. 216, no. 1-2, pp. 39–50, 2009. View at Publisher · View at Google Scholar · View at Scopus
  53. J. W. Prineas and J. D. E. Parratt, “Oligodendrocytes and the early multiple sclerosis lesion,” Annals of Neurology, vol. 72, no. 1, pp. 18–31, 2012. View at Publisher · View at Google Scholar · View at Scopus
  54. Y. Zhou, Y. Wang, M. Kovacs, J. Jin, and J. Zhang, “Microglial activation induced by neurodegeneration: a proteomic analysis,” Molecular and Cellular Proteomics, vol. 4, no. 10, pp. 1471–1479, 2005. View at Publisher · View at Google Scholar · View at Scopus
  55. M. Smeyne, Y. Jiao, K. R. Shepherd, and R. J. Smeyne, “Glia cell number modulates sensitivity to MPTP in mice,” Glia, vol. 52, no. 2, pp. 144–152, 2005. View at Publisher · View at Google Scholar · View at Scopus
  56. M. Sawada, K. Imamura, and T. Nagatsu, “Role of cytokines in inflammatory process in Parkinson's disease,” Journal of Neural Transmission, Supplement, no. 70, pp. 373–381, 2006. View at Google Scholar · View at Scopus
  57. P. L. McGeer, S. Itagaki, B. E. Boyes, and E. G. McGeer, “Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains,” Neurology, vol. 38, no. 8, pp. 1285–1291, 1988. View at Publisher · View at Google Scholar · View at Scopus
  58. A. Gerhard, N. Pavese, G. Hotton et al., “In vivo imaging of microglial activation with 11C(R)-PK11195 PET in idiopathic Parkinson's disease,” Neurobiology of Disease, vol. 21, no. 2, pp. 404–412, 2006. View at Publisher · View at Google Scholar · View at Scopus
  59. A. Członkowska, M. Kohutnicka, I. Kurkowska-Jastrzȩbska, and A. Członkowski, “Microglial reaction in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson's disease mice model,” Neurodegeneration, vol. 5, no. 2, pp. 137–143, 1996. View at Publisher · View at Google Scholar · View at Scopus
  60. M. Kohutnicka, E. Lewandowska, I. Kurkowska-Jastrzebska, A. Członkowski, and A. Członkowska, “Microglial and astrocytic involvement in a murine model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP),” Immunopharmacology, vol. 39, no. 3, pp. 167–180, 1998. View at Publisher · View at Google Scholar · View at Scopus
  61. R. Lee Mosley, E. J. Benner, I. Kadiu et al., “Neuroinflammation, oxidative stress, and the pathogenesis of Parkinson's disease,” Clinical Neuroscience Research, vol. 6, no. 5, pp. 261–281, 2006. View at Publisher · View at Google Scholar · View at Scopus
  62. J. W. Langston, L. S. Forno, J. Tetrud, A. G. Reeves, J. A. Kaplan, and D. Karluk, “Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure,” Annals of Neurology, vol. 46, no. 4, pp. 598–605, 1999. View at Google Scholar
  63. T. H. Hamza, C. P. Zabetian, A. Tenesa et al., “Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease,” Nature Genetics, vol. 42, no. 9, pp. 781–785, 2010. View at Publisher · View at Google Scholar · View at Scopus
  64. V. Y. Chock and R. G. Giffard, “Development of neonatal murine microglia In vitro: changes in response to lipopolysaccharide and ischemia-like injury,” Pediatric Research, vol. 57, no. 4, pp. 475–480, 2005. View at Publisher · View at Google Scholar · View at Scopus
  65. M. Lee, “Neurotransmitters and microglial-mediated neuroinflammation,” Current Protein and Peptide Science, vol. 14, no. 1, pp. 21–32, 2013. View at Publisher · View at Google Scholar · View at Scopus
  66. T. F. Pais, É. M. Szegő, O. Marques et al., “The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation,” EMBO Journal, vol. 32, no. 19, pp. 2603–2616, 2013. View at Publisher · View at Google Scholar · View at Scopus
  67. P. Mclaughlin, Y. Zhou, T. Ma et al., “Proteomic analysis of microglial contribution to mouse strain-dependent dopaminergic neurotoxicity,” Glia, vol. 53, no. 6, pp. 567–582, 2006. View at Publisher · View at Google Scholar · View at Scopus
  68. A. L. de Lella Ezcurra, M. Chertoff, C. Ferrari, M. Graciarena, and F. Pitossi, “Chronic expression of low levels of tumor necrosis factor-α in the substantia nigra elicits progressive neurodegeneration, delayed motor symptoms and microglia/macrophage activation,” Neurobiology of Disease, vol. 37, no. 3, pp. 630–640, 2010. View at Publisher · View at Google Scholar · View at Scopus
  69. M. Mogi, M. Harada, H. Narabayashi, H. Inagaki, M. Minami, and T. Nagatsu, “Interleukin (IL)-1β, IL-2, IL-4, IL-6 and transforming growth factor-α levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson's disease,” Neuroscience Letters, vol. 211, no. 1, pp. 13–16, 1996. View at Publisher · View at Google Scholar · View at Scopus
  70. C. C. Ferrari, M. C. Pott Godoy, R. Tarelli, M. Chertoff, A. M. Depino, and F. J. Pitossi, “Progressive neurodegeneration and motor disabilities induced by chronic expression of IL-1β in the substantia nigra,” Neurobiology of Disease, vol. 24, no. 1, pp. 183–193, 2006. View at Publisher · View at Google Scholar · View at Scopus
  71. M. C. P. Godoy, R. Tarelli, C. C. Ferrari, M. I. Sarchi, and F. J. Pitossi, “Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson's disease,” Brain, vol. 131, part 7, pp. 1880–1894, 2008. View at Publisher · View at Google Scholar · View at Scopus
  72. R. Gordon, V. Anantharam, and A. G. Kanthasamy, “Proteolytic activation of proapoptotic kinase protein kinase Cδ by tumor necrosis factor α death receptor signaling in dopaminergic neurons during neuroinflammation,” Journal of Neuroinflammation, vol. 9, article 82, 2012. View at Publisher · View at Google Scholar · View at Scopus
  73. K. Sriram, J. M. Matheson, S. A. Benkovic, D. B. Miller, M. I. Luster, and J. P. O'Callaghan, “Deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP-induced neurotoxicity: role of TNF-α1,” FASEB Journal, vol. 20, no. 6, pp. 670–682, 2006. View at Publisher · View at Google Scholar · View at Scopus
  74. D. K. Stone, A. D. Reynolds, R. L. Mosley, and H. E. Gendelman, “Innate and adaptive immunity for the pathobiology of Parkinson's disease,” Antioxidants and Redox Signaling, vol. 11, no. 9, pp. 2151–2166, 2009. View at Publisher · View at Google Scholar · View at Scopus
  75. S. H. Appel, D. R. Beers, and J. S. Henkel, “T cell-microglial dialogue in Parkinson's disease and amyotrophic lateral sclerosis: are we listening?” Trends in Immunology, vol. 31, no. 1, pp. 7–17, 2010. View at Publisher · View at Google Scholar · View at Scopus
  76. A. S. Harm, S. Cao, A. L. Rowse et al., “MHCII is required for α-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration,” Journal of Neuroscience, vol. 33, no. 23, pp. 9592–9600, 2013. View at Publisher · View at Google Scholar · View at Scopus
  77. A. Michelucci, T. Heurtaux, L. Grandbarbe, E. Morga, and P. Heuschling, “Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: effects of oligomeric and fibrillar amyloid-β,” Journal of Neuroimmunology, vol. 210, no. 1-2, pp. 3–12, 2009. View at Publisher · View at Google Scholar · View at Scopus
  78. B. Engelhardt, “The blood-central nervous system barriers actively control immune cell entry into the central nervous system,” Current Pharmaceutical Design, vol. 14, no. 16, pp. 1555–1565, 2008. View at Publisher · View at Google Scholar · View at Scopus
  79. J. I. Alvarez, A. Dodelet-Devillers, H. Kebir et al., “The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence,” Science, vol. 334, no. 6063, pp. 1727–1731, 2011. View at Publisher · View at Google Scholar · View at Scopus
  80. P. L. McGeer, T. Kawamata, D. G. Walker, H. Akiyama, I. Tooyama, and E. G. McGeer, “Microglia in degenerative neurological disease,” Glia, vol. 7, no. 1, pp. 84–92, 1993. View at Publisher · View at Google Scholar · View at Scopus
  81. V. Brochard, B. Combadière, A. Prigent et al., “Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease,” Journal of Clinical Investigation, vol. 119, no. 1, pp. 182–192, 2009. View at Publisher · View at Google Scholar · View at Scopus
  82. K. U. Tufekci, S. Genc, and K. Genc, “The endotoxin-induced neuroinflammation model of Parkinson's disease,” Parkinson's Disease, vol. 2011, Article ID 487450, 25 pages, 2011. View at Publisher · View at Google Scholar · View at Scopus
  83. A. D. Reynolds, R. Banerjee, J. Liu, H. E. Gendelman, and R. L. Mosley, “Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson's disease,” Journal of Leukocyte Biology, vol. 82, no. 5, pp. 1083–1094, 2007. View at Publisher · View at Google Scholar · View at Scopus
  84. A. D. Reynolds, D. K. Stone, J. A. L. Hutter, E. J. Benner, R. L. Mosley, and H. E. Gendelman, “Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease,” Journal of Immunology, vol. 184, no. 5, pp. 2261–2271, 2010. View at Publisher · View at Google Scholar · View at Scopus
  85. A. L. Bartels, A. T. M. Willemsen, R. Kortekaas et al., “Decreased blood-brain barrier P-glycoprotein function in the progression of Parkinson's disease, PSP and MSA,” Journal of Neural Transmission, vol. 115, no. 7, pp. 1001–1009, 2008. View at Publisher · View at Google Scholar · View at Scopus
  86. V. Appay and S. L. Rowland-Jones, “RANTES: a versatile and controversial chemokine,” Trends in Immunology, vol. 22, no. 2, pp. 83–87, 2001. View at Publisher · View at Google Scholar · View at Scopus
  87. M. Rentzos, C. Nikolaou, E. Andreadou et al., “Circulating interleukin-15 and RANTES chemokine in Parkinson's disease,” Acta Neurologica Scandinavica, vol. 116, no. 6, pp. 374–379, 2007. View at Publisher · View at Google Scholar · View at Scopus
  88. C. H. Stevens, D. Rowe, M. Morel-Kopp et al., “Reduced T helper and B lymphocytes in Parkinson's disease,” Journal of Neuroimmunology, vol. 252, no. 1-2, pp. 95–99, 2012. View at Publisher · View at Google Scholar · View at Scopus
  89. F. Niwa, N. Kuriyama, M. Nakagawa, and J. Imanishi, “Effects of peripheral lymphocyte subpopulations and the clinical correlation with Parkinson's disease,” Geriatrics and Gerontology International, vol. 12, no. 1, pp. 102–107, 2012. View at Publisher · View at Google Scholar · View at Scopus
  90. N. Funk, P. Wieghofer, S. Grimm et al., “Characterization of peripheral hematopoietic stem cells and monocytes in Parkinson's disease,” Movement Disorders, vol. 28, no. 3, pp. 392–395, 2013. View at Publisher · View at Google Scholar · View at Scopus
  91. E. C. Shin, S. E. Cho, D. Lee et al., “Expression patterns of α-synuclein in human hematopoietic cells and in Drosophila at different developmental stages,” Molecules and Cells, vol. 10, no. 1, pp. 65–70, 2000. View at Publisher · View at Google Scholar · View at Scopus
  92. A. I. Su, T. Wiltshire, S. Batalov et al., “A gene atlas of the mouse and human protein-encoding transcriptomes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 16, pp. 6062–6067, 2004. View at Publisher · View at Google Scholar · View at Scopus
  93. S. A. Austin, A. M. Floden, E. J. Murphy, and C. K. Combs, “α-synuclein expression modulates microglial activation phenotype,” Journal of Neuroscience, vol. 26, no. 41, pp. 10558–10563, 2006. View at Publisher · View at Google Scholar · View at Scopus
  94. C. Wu, C. Orozco, J. Boyer et al., “BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources,” Genome Biology, vol. 10, no. 11, article R130, 2009. View at Publisher · View at Google Scholar · View at Scopus
  95. C. C. Cardoso, A. C. Pereira, C. de Sales Marques, and M. O. Moraes, “Leprosy susceptibility: genetic variations regulate innate and adaptive immunity, and disease outcome,” Future Microbiology, vol. 6, no. 5, pp. 533–549, 2011. View at Publisher · View at Google Scholar · View at Scopus
  96. D. Trabzuni, M. Ryten, W. Emmett et al., “Fine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus,” PLoS ONE, vol. 8, no. 8, Article ID e70724, 2013. View at Publisher · View at Google Scholar · View at Scopus
  97. M. Hirotani, C. Maita, M. Niino et al., “Correlation between DJ-1 levels in the cerebrospinal fluid and the progression of disabilities in multiple sclerosis patients,” Multiple Sclerosis, vol. 14, no. 8, pp. 1056–1060, 2008. View at Publisher · View at Google Scholar · View at Scopus
  98. K. M. Semchuk, E. J. Love, and R. G. Lee, “Parkinson's disease: a test of the multifactorial etiologic hypothesis,” Neurology, vol. 43, no. 6, pp. 1173–1180, 1993. View at Publisher · View at Google Scholar · View at Scopus
  99. H. Vlajinac, E. Dzoljic, J. Maksimovic, J. Marinkovic, S. Sipetic, and V. Kostic, “Infections as a risk factor for Parkinson's disease: a case-control study,” International Journal of Neuroscience, vol. 123, no. 5, pp. 329–332, 2013. View at Publisher · View at Google Scholar · View at Scopus
  100. C . M . L. Tomé, T. Tyson, N . L. Rey, S. Grathwohl, M. Britschgi, and P. Brundin, “Inflammation and α-synuclein's prion-like behavior in Parkinson's disease—is there a link?” Molecular Neurobiology, vol. 47, no. 2, pp. 561–574, 2013. View at Publisher · View at Google Scholar
  101. C. W. Olanow and P. Brundin, “Parkinson's disease and alpha synuclein: is Parkinson's disease a prion-like disorder?” Movement Disorders, vol. 28, no. 1, pp. 31–40, 2013. View at Publisher · View at Google Scholar · View at Scopus
  102. C. S. Lee, C. Won, H. Yoo et al., “Inhibition of double-stranded RNA-induced inducible nitric oxide synthase expression by fraxinellone and sauchinone in murine microglia,” Biological and Pharmaceutical Bulletin, vol. 32, no. 11, pp. 1870–1874, 2009. View at Publisher · View at Google Scholar · View at Scopus
  103. D. Ha, D. K. Stone, R. L. Mosley, and H. E. Gendelman, “Immunization strategies for Parkinson's disease,” Parkinsonism and Related Disorders, vol. 18, no. 1, pp. S218–S221, 2012. View at Google Scholar · View at Scopus
  104. M. K. McCoy, K. A. Ruhn, T. N. Martinez, F. E. McAlpine, A. Blesch, and M. G. Tansey, “Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats,” Molecular Therapy, vol. 16, no. 9, pp. 1572–1579, 2008. View at Publisher · View at Google Scholar · View at Scopus
  105. A. S. Harms, C. J. Barnum, K. A. Ruhn et al., “Delayed dominant-negative TNF gene therapy halts progressive loss of nigral dopaminergic neurons in a rat model of parkinson's disease,” Molecular Therapy, vol. 19, no. 1, pp. 46–52, 2011. View at Publisher · View at Google Scholar · View at Scopus
  106. H. Chen, S. M. Zhang, M. A. Hernán et al., “Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease,” Archives of Neurology, vol. 60, no. 8, pp. 1059–1064, 2003. View at Publisher · View at Google Scholar
  107. M. Etminan, B. C. Carleton, and A. Samii, “Non-steroidal anti-inflammatory drug use and the risk of Parkinson disease: a retrospective cohort study,” Journal of Clinical Neuroscience, vol. 15, no. 5, pp. 576–577, 2008. View at Publisher · View at Google Scholar · View at Scopus
  108. A. Samii, M. Etminan, M. O. Wiens, and S. Jafari, “NSAID use and the risk of parkinsons disease: systematic review and meta-analysis of observational studies,” Drugs & Aging, vol. 26, no. 9, pp. 769–779, 2009. View at Publisher · View at Google Scholar · View at Scopus
  109. X. Gao, H. Chen, M. A. Schwarzschild, and A. Ascherio, “Use of ibuprofen and risk of Parkinson disease,” Neurology, vol. 76, no. 10, pp. 863–869, 2011. View at Publisher · View at Google Scholar · View at Scopus
  110. B. Liu, L. Du, and J. S. Hong, “Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation,” The Journal of Pharmacology and Experimental Therapeutics, vol. 293, no. 2, pp. 607–617, 2000. View at Google Scholar · View at Scopus
  111. A. Castaño, A. J. Herrera, J. Cano, and A. Machado, “The degenerative effect of a single intranigral injection of LPS on the dopaminergic system is prevented by dexamethasone, and not mimicked by rh-TNF-α IL-1β IFN-γ,” Journal of Neurochemistry, vol. 81, no. 1, pp. 150–157, 2002. View at Publisher · View at Google Scholar · View at Scopus
  112. H. Kim and Y. Suh, “Minocycline and neurodegenerative diseases,” Behavioural Brain Research, vol. 196, no. 2, pp. 168–179, 2009. View at Publisher · View at Google Scholar · View at Scopus
  113. L. Lu, F. Li, and X. Wang, “Novel anti-inflammatory and neuroprotective agents for Parkinson's disease,” CNS and Neurological Disorders—Drug Targets, vol. 9, no. 2, pp. 232–240, 2010. View at Publisher · View at Google Scholar · View at Scopus
  114. M. Lee, V. Tazzari, D. Giustarini et al., “Effects of hydrogen sulfide-releasing L-DOPA derivatives on glial activation: potential for treating Parkinson disease,” The Journal of Biological Chemistry, vol. 285, no. 23, pp. 17318–17328, 2010. View at Publisher · View at Google Scholar · View at Scopus
  115. R. Sánchez-Pernaute, A. Ferree, O. Cooper, M. Yu, A. Brownell, and O. Isacson, “Selective COX-2 inhibition prevents progressive dopamine neuron degeneration in a rat model of Parkinson's disease,” Journal of Neuroinflammation, vol. 1, no. 1, article 6, 2004. View at Publisher · View at Google Scholar · View at Scopus
  116. P. Teismann, “COX-2 in the neurodegenerative process of Parkinson's disease,” BioFactors, vol. 38, no. 6, pp. 395–397, 2012. View at Publisher · View at Google Scholar · View at Scopus
  117. G. Paul and S. V. Anisimov, “The secretome of mesenchymal stem cells: potential implications for neuroregeneration,” Biochimie, vol. 95, no. 12, pp. 2246–2256, 2013. View at Publisher · View at Google Scholar · View at Scopus