Letter | Published:

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

Nature volume 494, pages 9094 (07 February 2013) | Download Citation


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


Primary accessions

Gene Expression Omnibus

Data deposits

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


  1. 1.

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

  2. 2.

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

  3. 3.

    , , & Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219, 979–980 (1983)

  4. 4.

    & Immune activation in brain aging and neurodegeneration: too much or too little? Neuron 64, 110–122 (2009)

  5. 5.

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

  6. 6.

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

  7. 7.

    & 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)

  8. 8.

    & Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr. Opin. Neurobiol. 20, 588–594 (2010)

  9. 9.

    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)

  10. 10.

    , , , & 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)

  11. 11.

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

  12. 12.

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

  13. 13.

    , , & αB-crystallin is expressed in non-lenticular tissues and accumulates in Alexander’s disease brain. Cell 57, 71–78 (1989)

  14. 14.

    , , & Suppression of GFAP toxicity by αB-crystallin in mouse models of Alexander disease. Hum. Mol. Genet. 18, 1190–1199 (2009)

  15. 15.

    & Protocol for the MPTP mouse model of Parkinson’s disease. Nature Protocols 2, 141–151 (2007)

  16. 16.

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

  17. 17.

    , , , & An ADIOL-ERβ-CtBP transrepression pathway negatively regulates microglia-mediated inflammation. Cell 145, 584–595 (2011)

  18. 18.

    , & Nuclear receptors, inflammation, and neurodegenerative diseases. Adv. Immunol. 106, 21–59 (2010)

  19. 19.

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

  20. 20.

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

  21. 21.

    , & Characterization of astrocyte-specific conditional knockouts. Genesis 45, 292–299 (2007)

  22. 22.

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

  23. 23.

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

  24. 24.

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

  25. 25.

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

  26. 26.

    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)

  27. 27.

    , & 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)

  28. 28.

    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)

  29. 29.

    , & High-yield isolation of murine microglia by mild trypsinization. Glia 44, 183–189 (2003)

  30. 30.

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

  31. 31.

    , , , & Identification of nigral dopaminergic neuron-enriched genes in adult rats. Neurobiol. Aging 32, 313–326 (2011)

  32. 32.

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

  33. 33.

    & 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)

Download references


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.

Author information

Author notes

    • Wei Shao
    •  & Shu-zhen Zhang

    These authors contributed equally to this work.


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

    • Mi Tang
    •  & Gang Hu
  3. National Eye Institute, NIH, Bethesda, Maryland 20892, 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, Illinois 60637, 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


  1. Search for Wei Shao in:

  2. Search for Shu-zhen Zhang in:

  3. Search for Mi Tang in:

  4. Search for Xin-hua Zhang in:

  5. Search for Zheng Zhou in:

  6. Search for Yan-qing Yin in:

  7. Search for Qin-bo Zhou in:

  8. Search for Yuan-yuan Huang in:

  9. Search for Ying-jun Liu in:

  10. Search for Eric Wawrousek in:

  11. Search for Teng Chen in:

  12. Search for Sheng-bin Li in:

  13. Search for Ming Xu in:

  14. Search for Jiang-ning Zhou in:

  15. Search for Gang Hu in:

  16. Search for Jia-wei Zhou in:


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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jia-wei Zhou.

Supplementary information

PDF files

  1. 1.

    Supplementary Figures

    This file contains Supplementary Figures 1-19.

Excel files

  1. 1.

    Supplementary Data

    This file contains Supplementary Table 1.

About this article

Publication history






Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.