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

Nature. 2013 Feb 7;494(7435):90-4. doi: 10.1038/nature11748. Epub 2012 Dec 16.


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 neuroinflammation. 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 neurotoxicity. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / immunology*
  • Astrocytes / metabolism*
  • Dopaminergic Neurons / drug effects
  • Immunity, Innate / drug effects
  • Inflammation / chemically induced
  • Inflammation / genetics
  • Inflammation / immunology*
  • Inflammation / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microglia / cytology
  • Microglia / immunology
  • Neuroprotective Agents / metabolism
  • Quinpirole / pharmacology
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / deficiency
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / metabolism*
  • Substantia Nigra / cytology
  • Substantia Nigra / drug effects
  • alpha-Crystallin B Chain / genetics
  • alpha-Crystallin B Chain / metabolism*


  • Cryab protein, mouse
  • Neuroprotective Agents
  • Receptors, Dopamine D2
  • alpha-Crystallin B Chain
  • Quinpirole
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Associated data

  • GEO/GSE41638