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Microglial cells and Parkinson’s disease

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Abstract

Chronic inflammation mediated by microglial cells is the fundamental process contributing to the death of dopamine (DA)-producing neurons in the brain. Production of inflammatory products by these microglial cells characterizes the slow destructive process in Parkinson’s disease (PD). The activation of microglial cells and the generation of pro-inflammatory cytokines that characterize PD are mediated by several different signaling pathways, with the activation of the respiratory burst by microglial cells being a critical event in the ultimate toxicity of DA-neurons. The work on our lab is concerned with understanding the mechanisms of activation, response, and therapeutic targets of microglial cells, with the aim to provide more effective treatments for PD and other inflammatory diseases of the CNS.

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References

  1. Nelson PT, Soma A, Lavi E. Microglia in diseases of the central nervous system. Ann Med. 2002;34:491–500.

    Article  PubMed  CAS  Google Scholar 

  2. Liu B, Hong J-S. Role of microglia in inflammation-mediated neurodegenerative disease: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther. 2003;304:1–7.

    Article  PubMed  CAS  Google Scholar 

  3. Guillemin GJ, Brew BJ. Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification. J Leukoc Biol. 2004;75:388–97.

    Article  PubMed  CAS  Google Scholar 

  4. Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron. 2003;39:889–909.

    Article  PubMed  CAS  Google Scholar 

  5. Bartels AL, Leenders KL. Neuroinflammation in the pathophysiology of Parkinson’s disease: evidence from animal models to human in vivo studies with [(11)C]-PK11195 PET. Mov Disord. 2007;22:1852–6.

    Article  PubMed  Google Scholar 

  6. Cicchetti F, Brownell AL, Williams K, et al. Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging. Eur J Neurosci. 2002;15:991–8.

    Article  PubMed  CAS  Google Scholar 

  7. Loeffler DA, DeMaggio AJ, Juneau PL, et al. Effects of enhanced striatal dopamine turnover in vivo on glutathione oxidation. Clin Neuropharmacol. 1994;17:370–9.

    Article  PubMed  CAS  Google Scholar 

  8. Ghosh A, Roy A, Liu X, et al. Selective inhibition of NF-kB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson’s disease. Proc Natl Acad Sci USA. 2007;104:18754–9.

    Article  PubMed  CAS  Google Scholar 

  9. McGeer PL, Itagaki S, Boyes BE, et al. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology. 1988;38:1285–91.

    PubMed  CAS  Google Scholar 

  10. Nagatsu T, Mogi M, Ichinose H, et al. Changes in cytokines and neurotrophins in Parkinson’s disease. J Neural Transm. 2000;60:277–90.

    Google Scholar 

  11. Mogi M, Harada M, Kondo T, et al. Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients. Neurosci Lett. 1994;180:147–50.

    Article  PubMed  CAS  Google Scholar 

  12. Bessler H, Djaldetti R, Salman H, et al. IL-1 beta, IL-2, IL-6 and TNF-alpha production by peripheral blood mononuclear cells from patients with Parkinson’s disease. Biomed Pharmacother. 1999;53:141–5.

    Article  PubMed  CAS  Google Scholar 

  13. Qureshi GA, Baig S, Bednar I, et al. Increased cerebrospinal fluid concentration of nitrite in Parkinson’s disease. Neuroreport. 1995;6:1642–4.

    Article  PubMed  CAS  Google Scholar 

  14. Hunot SG, Boissiere G, Faucheux B, et al. Nitric oxide synthase and neuronal vulnerability in Parkinson’s disease. Neuroscience. 1996;72:355–63.

    Article  PubMed  CAS  Google Scholar 

  15. Czlonkowska A, Kohutnicka M, Kurkowska-Jastrzebska I, et al. Microglial reaction in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson’s disease mice model. Neurodegeneration. 1996;5:137–43.

    Article  PubMed  CAS  Google Scholar 

  16. Wu DC, Jackson-Lewis V, Vila M, et al. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci. 2002;22:1763–71.

    PubMed  CAS  Google Scholar 

  17. Kim WG, Mohney RP, Wilson B, et al. Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia. J Neurosci. 2000;20:6309–16.

    PubMed  CAS  Google Scholar 

  18. Fujiwara N, Kobayashi K Macrophages in inflammation. Curr Drug Targets Inflamm Allergy. 2005;4:281–6.

    Article  PubMed  CAS  Google Scholar 

  19. Gordon S Alternative activation of macrophages. Nat Rev Immunol. 2003;3:23–35.

    Article  PubMed  CAS  Google Scholar 

  20. Janeway CA, Walport TP, Shlomchik M Immunobiology: the immune system in health and disease. New York, New York: Garland Science Publishing; 2005.

    Google Scholar 

  21. Piani D, Frei K, Do KQ, et al. Murine brain macrophages induced NMDA receptor mediated neurotoxicity in vitro by secreting glutamate. Neurosci Lett. 1991;133:159–62.

    Article  PubMed  CAS  Google Scholar 

  22. Taylor DL, Jones F, Kubota ES, et al. Stimulation of microglial metabotropic glutamate receptor mGlu2 triggers tumor necrosis factor-α-induced neurotoxicity in concert with microglial-derived Fas ligand. J Neurosci. 2005;25:2952–64.

    Article  PubMed  CAS  Google Scholar 

  23. Floden AM, Li S, Combs CK β-Amyloid-stimulated microglia induce neuron death via synergistic stimulation of tumor necrosis factor alpha and NMDA receptors. J Neurosci. 2005;25:2566–75.

    Article  PubMed  CAS  Google Scholar 

  24. Chao CC, Hu S, Molitor TW, et al. Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. J Immunol. 1992;149:2736–41.

    PubMed  CAS  Google Scholar 

  25. Tikka TM, Koistinaho JE Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol. 2001;166:7527–33.

    PubMed  CAS  Google Scholar 

  26. Kingham PJ, Pocock JM Microglial secreted cathepsin B induces neuronal apoptosis. J Neurochem. 2001;76:1475–84.

    Article  PubMed  CAS  Google Scholar 

  27. Piani D., Fontana A Involvement of the cystine transport system xc- in the macrophage- induced glutamate-dependent cytotoxicity to neurons. J Immunol. 1994;152:3578–85.

    PubMed  CAS  Google Scholar 

  28. Thirumangalakudi L, Yin L, Rao HV, et al. IL-8 induces expression of matrix metalloproteinases, cell cycle and pro-apoptotic proteins, and cell death in cultured neurons. J Alzheimers Dis. 2007;11:305–11.

    PubMed  CAS  Google Scholar 

  29. Colton CA, Gilbert DL Production of superoxide anions by a CNS macrophage, the microglia. FEBS Lett. 1987;223:284–8.

    Article  PubMed  CAS  Google Scholar 

  30. Bronstein DM, Perez-Otano I, Sun V, Mullis-Sawin SB, et al. Glia-dependent neurotoxicity and neuroprotection in mesencephalic cultures. Brain Res. 1995;704:112–6.

    Article  PubMed  CAS  Google Scholar 

  31. Araki E, Forster C, Dubinsky JM, et al. Cyclooxygenase-2 inhibitor NS-398 protects neuronal cultures from lipopolysaccharide-induced neurotoxicity. Stroke. 2001;32:2370–5.

    Article  PubMed  CAS  Google Scholar 

  32. Liu B, Gao HM, Wang J-Y, et al. Role of nitric oxide in inflammation-mediated neurodegeneration. Ann NY Acad Sci. 2002;962:256–63.

    Google Scholar 

  33. Qin L, Liu YX, Cooper CL, et al. Microglia enhance beta-amyloid peptide-induced toxicity in cortical and mesencephalic neurons by producing reactive oxygen species. J Neurochem. 2002;83:973–83.

    Article  PubMed  CAS  Google Scholar 

  34. Zhang W, Wang T, Pei Z, et al. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J. 2005;19:533–42.

    Article  PubMed  CAS  Google Scholar 

  35. Itzhak Y, Martin JL, Ali SF Methamphetamine- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity in inducible nitric oxide synthase-deficient mice. Synapse. 1999;34:305–12.

    Article  PubMed  CAS  Google Scholar 

  36. Liberatore GT, Jackson-Lewis V, Vukosavic S, et al. Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med. 1999;5:1403–9.

    Article  PubMed  CAS  Google Scholar 

  37. Dehmer T, Lindenau J, Haid S, et al. Deficiency of inducible nitric oxide synthase protects against MPTP toxicity in vivo. J Neurochem. 2000;74:2213–6.

    Article  PubMed  CAS  Google Scholar 

  38. Du Y, Ma Z, Lin S, et al. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. Proc Natl Acad Sci USA. 2001;98:14669–74.

    Article  PubMed  CAS  Google Scholar 

  39. Factor SA, Sanchez-Ramos J, Weiner WJ Trauma as an etiology of parkinsonism: a historical review of the concept. Mov Disord. 1988;3:30–6.

    Article  PubMed  CAS  Google Scholar 

  40. Casals J, Elizan TS, Yahr WH Postencephalitic parkinsonism. J Neural Transm. 1998;105:645–76.

    Article  PubMed  CAS  Google Scholar 

  41. Ling Z, Gayle DA, Ma SY, et al. In utero bacterial endotoxin exposure causes loss of tyrosine hydroxylase neurons in the postnatal rat midbrain. Mov Disord. 2002;17:116–24.

    Article  PubMed  Google Scholar 

  42. Jackson-Lewis V, Smeyne RJ MPTP and SNpc DA neuronal vulnerability: role of dopamine, superoxide and nitric oxide in neurotoxicity. Minireview Neurotox Res. 2005;7:193–202.

    CAS  Google Scholar 

  43. Liu Y, Qin L, Li G, et al. Dextromethorphan protects dopamanergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. J Pharmacol Exp Ther. 2003;305:1–7.

    Article  CAS  Google Scholar 

  44. Qian L, Block ML, Wei SJ, et al. Interleukin-10 protects lipopolysaccharide-induced neurotoxicity in primary midbrain cultures by inhibiting the function of NADPH oxidase. J Pharmacol Exp Ther. 2006;319:44–52.

    Article  PubMed  CAS  Google Scholar 

  45. Qian L, Tan KS, Wei SJ, et al. Microglia-mediated neurotoxicity is inhibited by morphine through an opioid receptor-independent reduction of NADPH oxidase activity. J Immunol. 2007;179:1198–209.

    PubMed  CAS  Google Scholar 

  46. Sanlioglu S, Williams CM, Samavati L, et al. Lipopolysaccharide induces Rac1-dependent reactive oxygen species formation and coordinates tumor necrosis factor-alpha secretion through IKK regulation of NF-_B. J Biol Chem. 2001;276:30188–1098.

    Article  PubMed  CAS  Google Scholar 

  47. Hsu HY, Wen MH Lipopolysaccharide-mediated reactive oxygen species and signal transduction in the regulation of IL-1 gene expression. J Biol Chem. 2002;277:22131–9.

    Article  PubMed  CAS  Google Scholar 

  48. Qin L, Liu Y, Wang T, et al. NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem. 2004;279:1415–21.

    Article  PubMed  CAS  Google Scholar 

  49. Groemping Y, Rittinger K Activation and assembly of the NADPH oxidase: a structural perspective. Biochem J. 2005;386:401–16.

    Article  PubMed  CAS  Google Scholar 

  50. Qian L, Hong JS, Flood PM Role of microglia in inflammation-mediated degeneration of dopaminergic neurons: neuroprotective effect of interleukin 10. J Neural Transm Suppl. 2006;70:367–71.

    Article  PubMed  CAS  Google Scholar 

  51. Barger SW, Basile AS Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function. J Neurochem. 2001;76:846–54.

    Article  PubMed  CAS  Google Scholar 

  52. Heyes MP, Achim CL, Wiley CA, et al. Human microglia convert L-tryptophan into the neurotoxin quinolinic acid. Biochem J. 1996;320:595–7.

    PubMed  CAS  Google Scholar 

  53. Wu S-Z, Bodles AM, Porter MM, et al. Induction of serine racemase expression and D-serine release from microglia by amyloid β-peptide. J Neuroinflammation. 2004;1:2–12.

    Article  PubMed  Google Scholar 

  54. Qian L, Gao X, Pei Z, et al. NADPH oxidase inhibitor DPI is neuroprotective at femtomolar concentrations through inhibition of microglia over-activation. Parkinsonism Relat Disord. 2007;13:S316–20.

    Article  PubMed  Google Scholar 

  55. Rock RB, Peterson PK Microglia as a pharmacological target in infectious and inflammatory diseases of the brain. J Neuroimmune Pharmacol. 2006;1:117–26.

    Article  PubMed  Google Scholar 

  56. Mosley RL, Benner EJ, Kadiu I, et al. Neuroinflammation, oxidative stress and the pathogenesis of Parkinson’s disease. Clin Neurosci Res. 2006;6:261–81.

    Article  PubMed  CAS  Google Scholar 

  57. Reynolds AD, Banerjee R, Liu J, et al. Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson’s disease. J Leukoc Biol. 2007;82:1083–94.

    Article  PubMed  CAS  Google Scholar 

  58. Arimoto T, Choi DY, Lu X, et al. Interleukin-10 protects against inflammation-mediated degeneration of dopaminergic neurons in substantia nigra. Neurobiol Aging. 2006;28:894–906.

    Article  CAS  Google Scholar 

  59. Zhu Y, Yang GY, Ahlemeyer B, et al. Transforming growth factor-beta 1 increases bad phosphorylation and protects neurons against damage. J Neurosci. 2002;22:3898–909.

    PubMed  CAS  Google Scholar 

  60. Ruocco A, Nicole O, Docagne F, et al. A transforming growth factor-beta antagonist unmasks the neuroprotective role of this endogenous cytokine in excitotoxic and ischemic brain injury. J Cereb Blood Flow Metab. 1999;19:1345–53.

    Article  PubMed  CAS  Google Scholar 

  61. Prehn JH, Bindokas VP, Marcuccilli CJ, et al. Regulation of neuronal Bcl2 protein expression and calcium homeostasis by transforming growth factor type beta confers wide-ranging protection on rat hippocampal neurons. Proc Natl Acad Sci USA. 1994;91:12599–603.

    Article  PubMed  CAS  Google Scholar 

  62. Szczepanik M, Tutaj M, Bryniarski K, et al. Epicutaneously induced TGF-beta-dependent tolerance inhibits experimental autoimmune encephalomyelitis. J Neuroimmunol. 2005;164:105–14.

    Article  PubMed  CAS  Google Scholar 

  63. Unsicker K, Krieglstein K TGF-betas and their roles in the regulation of neuron survival. Adv Exp Med Biol. 2002;513:353–74.

    PubMed  CAS  Google Scholar 

  64. Henrich-Noack P, Prehn JH, Krieglstein J TGF-beta 1 protects hippocampal neurons against degeneration caused by transient global ischemia. Dose–response relationship and potential neuroprotective mechanisms. Stroke. 1996;27:1609–14.

    PubMed  CAS  Google Scholar 

  65. Carmona-Cuenca I, Herrera B, Ventura JJ, et al. EGF blocks NADPH oxidase activation by TGF-beta in fetal rat hepatocytes, impairing oxidative stress, and cell death. J Cell Physiol. 2006;207:322–30.

    Article  PubMed  CAS  Google Scholar 

  66. Zhuge J, Cederbaum AI Increased toxicity by transforming growth factor-beta 1 in liver cells overexpressing CYP2E1. Free Radic Biol Med. 2006;41:1100–12.

    Article  PubMed  CAS  Google Scholar 

  67. Suzumura A, Sawada M, Yamamoto H, et al. Transforming growth factor-beta suppresses activation and proliferation of microglia in vitro. J Immunol. 1993;151:2150–8.

    PubMed  CAS  Google Scholar 

  68. Herrera-Molina R, von Bernhardi R Transforming growth factor-beta 1 produced by hippocampal cells modulates microglial reactivity in culture. Neurobiol Dis. 2005;19:229–36.

    Article  PubMed  CAS  Google Scholar 

  69. Dunker N, Schuster N, Krieglstein K TGF-beta modulates programmed cell death in the retina of the developing chick embryo. Development. 2001;128:1933–42.

    PubMed  CAS  Google Scholar 

  70. Krieglstein K, Richter S, Farkas L, et al. Reduction of endogenous transforming growth factors beta prevents ontogenetic neuron death. Nat Neurosci. 2000;3:1085–90.

    Article  PubMed  CAS  Google Scholar 

  71. Basu A, Krady JK, Enterline JR, et al. Transforming growth factor beta1 prevents IL-1beta-induced microglial activation, whereas TNFalpha- and IL-6-stimulated activation are not antagonized. Glia. 2002;40:109–20.

    Article  PubMed  Google Scholar 

  72. Buisson A, Nicole O, Docagne F, et al. Up-regulation of a serine protease inhibitor in astrocytes mediates the neuroprotective activity of transforming growth factor beta1. FASEB J. 1998;12:1683–91.

    PubMed  CAS  Google Scholar 

  73. Li Qian, Wei SJ, Zhang D, et al. Potent anti-inflammatory and neuroprotective effects of TGFβ1 are mediated through the inhibition of ERK and p47phox-Ser345 phosphorylation and translocation in microglia. J Immunol. 2008; in press.

  74. Liu B, Du L, Hong JS Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation. J Pharmacol Exp Ther. 2000;293:607–17.

    PubMed  CAS  Google Scholar 

  75. Liu Y, Qin L, Li G, et al. Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. J Pharmacol Exp Ther. 2003;305:212–8.

    Article  PubMed  CAS  Google Scholar 

  76. Liu B, Jiang JW, Wilson B, et al. Systemic infusion of naloxone reduces degeneration of rat substantia nigral dopaminergic neurons induced by intranigral injection of lipopolysaccharide. J Pharmacol Exp Ther. 2000;295:125–32.

    PubMed  CAS  Google Scholar 

  77. Qian L, Tan KS, Xu Z, et al. Microglia-mediated neurotoxicity is inhibited by morphine through mu-opioid receptor independent reduction of NADPH oxidase activity. J. Immunol. 2007;179:1198–209.

    PubMed  CAS  Google Scholar 

  78. Yamasaki H Pharmacology of sinomenine, an anti-rheumatic alkaloid from Sinomenium acutum. Acta Med Okayama. 1976;30:1–20.

    PubMed  CAS  Google Scholar 

  79. Feng CI, Chin Y, Wang NC, et al. The pharmacology of sinomenine VII. Effect of sinomenine on the gastro-intestinal movement and its mechanism. Yao Xue Xue Bao. 1965;12:492–5.

    PubMed  CAS  Google Scholar 

  80. Wang Y, Zhou L, Li R Study progress in Sinomenium acutum (Thunb.) Rehd. et Wils.. Zhong Yao Cai. 2002;25:209–11.

    PubMed  Google Scholar 

  81. Vieregge B, Resch K, Kaever V Synergistic effects of the alkaloid sinomenine in combination with the immunosuppressive drugs tacrolimus and mycophenolic acid. Planta Med. 1999;65:80–2.

    Article  PubMed  CAS  Google Scholar 

  82. Liu L, Buchner E, Beitze D, et al. Amelioration of rat experimental arthritides by treatment with the alkaloid sinmenine. Int J Immunopharmacol. 1996;18:529–43.

    Article  PubMed  CAS  Google Scholar 

  83. Liu L, Riese J, Resch K, Kaever V Impairment of macrophage eicosanoid and nitric oxide production by an alkaloid from Sinomenium acutum. Arzneimittelforschung. 1994;44:1223–6.

    PubMed  CAS  Google Scholar 

  84. Kondo Y, Takano F, Yoshida K, et al. Protection by sinomenine against endotoxin-induced fulminant hepatitis in galactosamine-sensitized mice. Biochem Pharmacol. 1994;48:1050–2.

    Article  PubMed  CAS  Google Scholar 

  85. Candinas D, Mark W, Kaever V, et al. Immunomodulatory effects of the alkaloid sinomenine in the high responder ACI-to-Lewis cardiac allograft model. Transplantation. 1996;62:1855–60.

    Article  PubMed  CAS  Google Scholar 

  86. Dang PM, Stensballe A, Boussetta T, et al. A specific p47phox -serine phosphorylated by convergent MAPKs mediates neutrophil NADPH oxidase priming at inflammatory sites. J Clin Invest. 2006;116:2033–43.

    Article  PubMed  CAS  Google Scholar 

  87. Thomas MP, Chartrand K, Reynolds A, et al. Ion channel blockade attenuates aggregated alpha synuclein induction of microglial reactive oxygen species: relevance for the pathogenesis of Parkinson’s disease. J Neurochem. 2007;100:503–19.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by NIH grant DE-13079 from the National Institute for Dental and Craniofacial Research, and was also supported in part by the Intramural Research Program of the NIH/NIEHS. I want to acknowledge and thank all the current and former members of the lab, whose inspiration and dedication have helped shape this work and all the ideas in the laboratory.

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Correspondence to Patrick M. Flood.

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Qian, L., Flood, P.M. Microglial cells and Parkinson’s disease. Immunol Res 41, 155–164 (2008). https://doi.org/10.1007/s12026-008-8018-0

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