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

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

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

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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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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.

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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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