Suppression Of Neuroinflammation By Astrocytic Dopamine D2Receptors Via αB-crystallin

Parkinson’s disease (PD), also called Parkinsonism, is a common centralnervous system chronic degenerative disease. The disease is commonly onset in theelders, especially people more than60years older. The disease is characterizedclinically by bradykinesia (slowness of movement)，muscular rigidity，tremor at rest，and Postural abnormalities. The typical pathological features are loss ofdopaminergic neurons in substantia nigra compact (SNc), the presence of Lewy’sBodies and the reduction of dopamine content in the striatum.Chronic neuroinflammation is a common feature of aging brain and someneurodegenerative disorders, including Parkinson’s disease (PD). However, themolecular mechanism underlying the regulation of innate immunity in the centralnervous system remains elusive. Here we show that astrocytic dopamine D2receptor(Drd2) modulates innate immunity through αB-crystallin (Cryab) that is known to suppress neuroinflammation. We demonstrate that knockout mice lacking Drd2showed remarkable inflammatory response in multiple CNS regions and increasedvulnerability of nigral dopaminergic neurons to neurotoxin1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. Astrocytes null forDrd2became hyper-responsive to immune stimuli with dramatic reduction in thelevel of Cryab. Ablation of Drd2preferentially in astrocytes robustly activatedastrocytes in the substantia nigra. Gain-or loss-of-function studies showed thatCryab is critical for Drd2-mediated modulation of innate immune response inastrocytes. Interestingly, we found that aberrant expression of Cryab in reactiveastrocytes in the ventral mesencephalon of PD patients. Furthermore, treatment ofwild-type mice with a selective Drd2agonist increased resistance of the nigraldopaminergic neurons to MPTP via partial suppression of inflammation. Our studysuggests that astrocytic Drd2activation normally suppresses neuroinflammation viaa Cryab-dependent manner and provides new strategy for targeting glia-mediatedpathogenesis in PD.Neuroglial cells are essential for the maintenance of brain homeostasis.Activated neuroglial cells contribute to immune deregulation and neuroinflammationwhich are associated with aging and a variety of neurodegenerative disorders,including Parkinson’s disease (PD). Dopamine D2receptor (Drd2) is primarilyexpressed in the caudate-putamen, nucleus accumbens, olfactory tubercle andprefrontal cerebral cortex. It is involved in learning and memory, reward and motorcontrol. Alterations in Drd2system have been implicated in PD. The progression ofPD and brain aging are accompanied with down-regulation of Drd2density.Drd2-deficient mice show PD-like locomotor and pathological features. Drd2agonists have been used as adjunctive therapy for PD. All these lines of evidencesuggest that Drd2may play important roles in the pathogenesis of PD. However, the potential impact of Drd2function on the inflammatory responses in PD has not beenevaluated. Recent data indicate that full sets of neurotransmitter receptors includingdopamine receptors are expressed in microglia and astrocytes, indicating that classicneurotransmitter signaling regulates communications between neurons and glial cells.Whether the deficits in dopamine receptor signaling affect interaction betweenimmune and neural system contributing to unbalanced brain homeostasis and diseaseprogression remains unknown.AIM: To investigate whether Drd2participates in glial response andneuroinflammation in PD, and further study the underlying mechanism.METHODS: Wild type and knockout mice, including global Drd1-/-and Drd2-/-nullmice and mutant mice (Drd3-/-) were injected with saline or MPTP induced PDmodels. Dopaminergic neurons, astrocytes and microglia were detected byimmunostaining of tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP),and ionized calcium binding adaptor molecule1(Iba1); immunostaining, westernblotting and qPCR was taken for the analysis of expression of cryab andinflammatory cytokines in astrocytes, which were dealt with Drd2agonists andantagonists during conditional medium.RESULTS:1. Drd2knockout mice were more sensitive to MPTP and other PD models:Drd2knockout induced the proliferation of astrocyte and microglia, andrelease of inflammatory factors, such as IL-1β, IL-6, IL-12β, COX-2andiNOS, while dopaminergic neurons had no significant effect; Drd2knockout pronounced activation of astrocyte and microglia after administration with MPTP, and Drd2deficient aggravated the loss ofdopaminergic neurons in SN.2. The proliferation of astrocyte and microglia in Drd1knockout mice was notsignificant.3. Expression of major inflammatory mediators, including IL-1β andinducible nitric oxide synthase (iNOS), were not significantly altered inmicroglia and neurons isolated from Drd2-null pups compared to WTcontrol.4. Cryab was significantly increased and formation of aggregation in PDpatients and Drd2is important for expression of Cryab.5. Overexpression of cryab increased resisitance of the nigral dopaminergicneurons to MPTP via partial suppression of inflammation.CONCLUSION: Drd2is important in the MPTP-induced astrocytic and micrglialresponse via Cryab and indicates that the therapeutic strategy targeting to astrocyticmodulation with Drd2or Cryab may offer a great potential for the development ofnew treatment for PD.