Chronic neuroinflammation commonly occurs in the brains of aged individuals, as well as in patients suffering from certain neurodegenerative disorders. Impairments in the brain function of the elderly are associated with the decreased abundance of the dopamine D2 receptor (DRD2). Noting that neuroglial cells, including astrocytes, express DRD2 and contribute to neuroinflammation, Shao et al. investigated whether defects in DRD2 signaling in glial cells contributed to a loss of brain homeostasis. Immunohistochemical analysis showed that neuroinflammation in aged DRD2-deficient mice was more severe than that in age-matched wild-type mice. This phenotype was associated with the increased abundance of mRNA and protein of proinflammatory mediators, including interleukin-1β and cyclooxygenase-2. In vitro analysis of different cell types isolated from brains showed that astrocytes, and not neurons or microglia, were more activated in DRD2-deficient mice than in wild-type mice and that they produced increased amounts of proinflammatory mediators. DRD2-deficient astrocytes showed enhanced responsiveness to immune stimuli compared with that of astrocytes from wild-type mice. In addition, aging-associated neuroinflammation was enhanced in mice with an astrocyte-specific deletion of Drd2 compared with that in wild-type mice. Microarray analysis revealed the decreased expression of the gene encoding αB-crystallin (CRYAB) in DRD2-deficient mice compared with that in wild-type mice. CRYAB is a small heat-shock protein with anti-inflammatory function. Knockdown of Cryab in cultured astrocytes resulted in increased production of proinflammatory factors, whereas the opposite effect was observed in DRD2-deficient astrocytes expressing exogenous CRYAB. In a neurotoxin-induced mouse model of Parkinson’s disease, pretreatment of mice with a DRD2-selective agonist led to protection of dopaminergic neurons from toxin-induced death. Together, these data suggest that DRD2 signaling in astrocytes mediates protection from neuroinflammation through a CRYAB-dependent mechanism.
W. Shao, S.-z. Zhang, M. Tang, X.-h. Zhang, Z. Zhou, Y.-q. Yin, Q.-b. Zhou, Y.-y. Huang, Y.-j. Liu, E. Wawrousek, T. Chen, S.-b. Li, M. Xu, J.-n. Zhou, G. Hu, J.-w. Zhou, Suppression of neuroinflammation by astrocytic dopamine D2 receptors via αB-crystallin. Nature 494, 90–94 (2013). [PubMed]