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Suppression of neuroinflammation by astrocytic dopamine D2 receptors via αB-crystallin

Nature volume 494, pages 90–94 (2013)Cite this article

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Abstract

Chronic neuroinflammation is a common feature of the ageing brain and some neurodegenerative disorders. However, the molecular and cellular mechanisms underlying the regulation of innate immunity in the central nervous system remain elusive. Here we show that the astrocytic dopamine D2 receptor (DRD2) modulates innate immunity through αB-crystallin (CRYAB), which is known to suppress neuroinflammation1,2. We demonstrate that knockout mice lacking Drd2 showed remarkable inflammatory response in multiple central nervous system regions and increased the vulnerability of nigral dopaminergic neurons to neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity3. Astrocytes null for Drd2 became hyper-responsive to immune stimuli with a marked reduction in the level of CRYAB. Preferential ablation of Drd2 in astrocytes robustly activated astrocytes in the substantia nigra. Gain- or loss-of-function studies showed that CRYAB is critical for DRD2-mediated modulation of innate immune response in astrocytes. Furthermore, treatment of wild-type mice with the selective DRD2 agonist quinpirole increased resistance of the nigral dopaminergic neurons to MPTP through partial suppression of inflammation. Our study indicates that astrocytic DRD2 activation normally suppresses neuroinflammation in the central nervous system through a CRYAB-dependent mechanism, and provides a new strategy for targeting the astrocyte-mediated innate immune response in the central nervous system during ageing and disease.

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Figure 1: More severe activation of astrocytes and microglia and pronounced inflammatory responses in global Drd2-deficient mice.
Figure 2: Astrocytes from global Drd2 −/− mice are hyper-responsive.
Figure 3: CRYAB overexpression suppresses Drd2 deficiency-induced inflammation.
Figure 4: In vivo activation of DRD2 inhibits astrogliosis and inflammation elicited by MPTP treatment.

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Gene Expression Omnibus

Data deposits

All original microarray data have been deposited in the NCBI Gene Expression Omnibus under accession number GSE41638.

References

  1. Bhat, R. & Steinman, L. Innate and adaptive autoimmunity directed to the central nervous system. Neuron 64, 123–132 (2009)

    Article  CAS  Google Scholar 

  2. Ousman, S. S. et al. Protective and therapeutic role for αB-crystallin in autoimmune demyelination. Nature 448, 474–479 (2007)

    Article  ADS  CAS  Google Scholar 

  3. Langston, J. W., Ballard, P., Tetrud, J. W. & Irwin, I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219, 979–980 (1983)

    Article  ADS  CAS  Google Scholar 

  4. Lucin, K. M. & Wyss-Coray, T. Immune activation in brain aging and neurodegeneration: too much or too little? Neuron 64, 110–122 (2009)

    Article  CAS  Google Scholar 

  5. Seeman, P. et al. Human brain dopamine receptors in children and aging adults. Synapse 1, 399–404 (1987)

    Article  CAS  Google Scholar 

  6. Kaasinen, V. et al. Age-related dopamine D2/D3 receptor loss in extrastriatal regions of the human brain. Neurobiol. Aging 21, 683–688 (2000)

    Article  CAS  Google Scholar 

  7. Antonini, A. & Leenders, K. L. Dopamine D2 receptors in normal human brain: effect of age measured by positron emission tomography (PET) and [11C]-raclopride. Ann. NY Acad. Sci. 695, 81–85 (1993)

    Article  ADS  CAS  Google Scholar 

  8. Zhang, Y. & Barres, B. A. Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr. Opin. Neurobiol. 20, 588–594 (2010)

    Article  CAS  Google Scholar 

  9. Bal, A. et al. Evidence for D2 receptor mRNA expression by striatal astrocytes in culture: in situ hybridization and polymerase chain reaction studies. Brain Res. Mol. Brain Res. 23, 204–212 (1994)

    Article  CAS  Google Scholar 

  10. Luo, X., Zhang, X., Shao, W., Yin, Y. & Zhou, J. Crucial roles of MZF-1 in the transcriptional regulation of apomorphine-induced modulation of FGF-2 expression in astrocytic cultures. J. Neurochem. 108, 952–961 (2009)

    Article  CAS  Google Scholar 

  11. Saijo, K. et al. A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137, 47–59 (2009)

    Article  CAS  Google Scholar 

  12. Zhuo, L. et al. hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo . Genesis 31, 85–94 (2001)

    Article  CAS  Google Scholar 

  13. Iwaki, T., Kume-Iwaki, A., Liem, R. K. & Goldman, J. E. αB-crystallin is expressed in non-lenticular tissues and accumulates in Alexander’s disease brain. Cell 57, 71–78 (1989)

    Article  CAS  Google Scholar 

  14. Hagemann, T. L., Boelens, W. C., Wawrousek, E. F. & Messing, A. Suppression of GFAP toxicity by αB-crystallin in mouse models of Alexander disease. Hum. Mol. Genet. 18, 1190–1199 (2009)

    Article  CAS  Google Scholar 

  15. Jackson-Lewis, V. & Przedborski, S. Protocol for the MPTP mouse model of Parkinson’s disease. Nature Protocols 2, 141–151 (2007)

    Article  CAS  Google Scholar 

  16. Rivest, S. Regulation of innate immune responses in the brain. Nature Rev. Immunol. 9, 429–439 (2009)

    Article  CAS  Google Scholar 

  17. Saijo, K., Collier, J. G., Li, A. C., Katzenellenbogen, J. A. & Glass, C. K. An ADIOL-ERβ-CtBP transrepression pathway negatively regulates microglia-mediated inflammation. Cell 145, 584–595 (2011)

    Article  CAS  Google Scholar 

  18. Saijo, K., Crotti, A. & Glass, C. K. Nuclear receptors, inflammation, and neurodegenerative diseases. Adv. Immunol. 106, 21–59 (2010)

    Article  CAS  Google Scholar 

  19. Brady, J. P. et al. αB-crystallin in lens development and muscle integrity: a gene knockout approach. Invest. Ophthalmol. Vis. Sci. 42, 2924–2934 (2001)

    CAS  PubMed  Google Scholar 

  20. Xu, M. et al. Dopamine D3 receptor mutant mice exhibit increased behavioral sensitivity to concurrent stimulation of D1 and D2 receptors. Neuron 19, 837–848 (1997)

    Article  CAS  Google Scholar 

  21. Casper, K. B., Jones, K. & McCarthy, K. D. Characterization of astrocyte-specific conditional knockouts. Genesis 45, 292–299 (2007)

    Article  CAS  Google Scholar 

  22. Cai, L. et al. Ethanol-induced neurodegeneration in NRSF/REST neuronal conditional knockout mice. Neuroscience 181, 196–205 (2011)

    Article  CAS  Google Scholar 

  23. Kelly, M. A. et al. Pituitary lactotroph hyperplasia and chronic hyperprolactinemia in dopamine D2 receptor-deficient mice. Neuron 19, 103–113 (1997)

    Article  CAS  Google Scholar 

  24. Drago, J. et al. Altered striatal function in a mutant mouse lacking D1A dopamine receptors. Proc. Natl Acad. Sci. USA 91, 12564–12568 (1994)

    Article  ADS  CAS  Google Scholar 

  25. Ousman, S. S. et al. Protective and therapeutic role for αB-crystallin in autoimmune demyelination. Nature 448, 474–479 (2007)

    Article  ADS  CAS  Google Scholar 

  26. Li, A. et al. Apomorphine-induced activation of dopamine receptors modulates FGF-2 expression in astrocytic cultures and promotes survival of dopaminergic neurons. FASEB J. 20, 1263–1265 (2006)

    Article  CAS  Google Scholar 

  27. Sauer, H., Rosenblad, C. & Bjorklund, A. Glial cell line-derived neurotrophic factor but not transforming growth factor beta 3 prevents delayed degeneration of nigral dopaminergic neurons following striatal 6-hydroxydopamine lesion. Proc. Natl Acad. Sci. USA 92, 8935–8939 (1995)

    Article  ADS  CAS  Google Scholar 

  28. Menet, V. et al. Inactivation of the glial fibrillary acidic protein gene, but not that of vimentin, improves neuronal survival and neurite growth by modifying adhesion molecule expression. J. Neurosci. 21, 6147–6158 (2001)

    Article  CAS  Google Scholar 

  29. Saura, J., Tusell, J. M. & Serratosa, J. High-yield isolation of murine microglia by mild trypsinization. Glia 44, 183–189 (2003)

    Article  Google Scholar 

  30. Guo, H. et al. Apomorphine induces trophic factors that support fetal rat mesencephalic dopaminergic neurons in cultures. Eur. J. Neurosci. 16, 1861–1870 (2002)

    Article  Google Scholar 

  31. Zhou, Q., Li, J., Wang, H., Yin, Y. & Zhou, J. Identification of nigral dopaminergic neuron-enriched genes in adult rats. Neurobiol. Aging 32, 313–326 (2011)

    Article  CAS  Google Scholar 

  32. Dimberg, A. et al. αB-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis. Blood 111, 2015–2023 (2008)

    Article  CAS  Google Scholar 

  33. Sauer, H. & Oertel, W. H. Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: A combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59, 401–415 (1994)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank B. Zhang and Y. J. Yan for technical assistance; L. Zhu for technical support in DNA microarray analysis; the Optical Imaging Center of ION and the Cell Biology Analysis Center of IBCB for technical support in confocal microscopy; T. L. Hagemann for providing the CRYAB construct; R. Quinlan for anti-CRYAB antibodies, Y. Q. Ding for providing the Drd1 and Drd2 gene null mice; we also thank Shanghai Research Center for Model Organisms for creating Drd2-floxed mice. This work was supported by grants from the Chinese Academy of Sciences, National Basic Research Program of China (nos 2011CBA00408 and 2011CB504102), Natural Science Foundation of China (nos 31021063 and 31123002), and Shanghai Metropolitan Fund for Research and Development.

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Author notes

  1. Wei Shao and Shu-zhen Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China ,

    Wei Shao, Shu-zhen Zhang, Mi Tang, Xin-hua Zhang, Zheng Zhou, Yan-qing Yin, Qin-bo Zhou, Yuan-yuan Huang, Ying-jun Liu & Jia-wei Zhou

  2. Department of Pharmacology, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, Jiangsu 210029, China,

    Mi Tang & Gang Hu

  3. National Eye Institute, NIH, Bethesda, 20892, Maryland, USA

    Eric Wawrousek

  4. Department of Forensic Science, Xi’an Jiaotong University School of Medicine, Xi’an, Shanxi 710061, China,

    Teng Chen & Sheng-bin Li

  5. Department of Anesthesia and Critical Care, University of Chicago, Chicago, 60637, Illinois, USA

    Ming Xu

  6. CAS Key Laboratory of Brain Function and Diseases, School of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, China ,

    Jiang-ning Zhou

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Contributions

W.S., S.-z.Z. conducted most of the in vivo and in vitro experiments and the data analysis, M.T., Z.Z. prepared cell cultures, Y.-q.Y. and Y.-j.L. contributed to cell cultures; X.-h.Z. and Q.-b.Z. contributed to pilot experiments. Y.-q.Y. and Y.-y.H. contributed to genotyping; E.W. provided CRYAB mutant mice; T.C, S.-b.L. and M.X. provided Drd3 mutant mice; J.-n.Z., G.H. provided pathological samples and/or advice and J.-w.Z. supervised the project and wrote the manuscript.

Corresponding author

Correspondence to Jia-wei Zhou.

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The authors declare no competing financial interests.

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Shao, W., Zhang, Sz., Tang, M. et al. Suppression of neuroinflammation by astrocytic dopamine D2 receptors via αB-crystallin. Nature 494, 90–94 (2013). https://doi.org/10.1038/nature11748

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