Cited by 154Neuroinflammation and Neurodegeneration MechanismsParkinson's Disease Mechanisms and TreatmentsNuclear Receptors and Signaling

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CD200-CD200R dysfunction exacerbates microglial activation and dopaminergic neurodegeneration in a rat model of Parkinson's disease

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Zhang, Shi, Wang, Xi-Jin, Tian, Li-Peng, Pan, Jing, Lu, Guo-Qiang, Zhang, Ying-Jie, Ding, Jian-Qing, Chen, Sheng-Di·2011·Journal of Neuroinflammation

DOI 10.1186/1742-2094-8-154PMC PMC3226566

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Abstract

BACKGROUND: Increasing evidence suggests that microglial activation may participate in the aetiology and pathogenesis of Parkinson's disease (PD). CD200-CD200R signalling has been shown to be critical for restraining microglial activation. We have previously shown that expression of CD200R in monocyte-derived macrophages, induced by various stimuli, is impaired in PD patients, implying an intrinsic abnormality of CD200-CD200R signalling in PD brain. Thus, further in vivo evidence is needed to elucidate the role of malfunction of CD200-CD200R signalling in the pathogenesis of PD. METHODS: 6-hydroxydopamine (6-OHDA)-lesioned rats were used as an animal model of PD. CD200R-blocking antibody (BAb) was injected into striatum to block the engagement of CD200 and CD200R. The animals were divided into three groups, which were treated with 6-OHDA/Veh (PBS), 6-OHDA/CAb (isotype control antibody) or 6-OHDA/BAb, respectively. Rotational tests and immunohistochemistry were employed to evaluate motor deficits and dopaminergic neurodegeneration in animals from each group. HPLC analysis was used to measure monoamine levels in striatum. Morphological analysis and quantification of CD11b- (or MHC II-) immunoreactive cells were performed to investigate microglial activation and possible neuroinflammation in the substantia nigra (SN). Finally, ELISA was employed to assay protein levels of proinflammatory cytokines. RESULTS: Compared with 6-OHDA/CAb or 6-OHDA/Veh groups, rats treated with 6-OHDA/BAb showed a significant increase in counts of contralateral rotation and a significant decrease in TH-immunoreactive (TH-ir) neurons in SN. A marked decrease in monoamine levels was also detected in 6-OHDA/BAb-treated rats, in comparison to 6-OHDA/Veh-treated ones. Furthermore, remarkably increased activation of microglia as well as up-regulation of proinflammatory cytokines was found concomitant with dopaminergic neurodegeneration in 6-OHDA/BAb-treated rats. CONCLUSIONS: This study shows that deficits in the CD200-CD200R system exacerbate microglial activation and dopaminergic neurodegeneration in a 6-OHDA-induced rat model of PD. Our results suggest that dysfunction of CD200-CD200R signalling may be involved in the aetiopathogenesis of PD.

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Figure 1 BAb exacerbates 6-OHDA-induced behavioural deficits. Contralateral rotation measurements following administration of apomorphine in each experimental group are shown in bar graph at 7 days and 21 days post-6-OHDA injection. Data are presented as mean ±S.E.M (n = 5 rats/group). (#)Statistical differences from 6-OHDA/Veh- or 6-OHDA/CAb-treated animals are P < 0.001.CC BY · PubMed Central

Figure 2 Neurodegeneration is exacerbated in the SN of hemi-parkinsonian rats. Animals (5 rats per groups) were sacrificed at 21-day post 6-OHDA injection to characterize and quantify loss of dopaminergic neurons in whole SN. (B-G) Representative sections (~24 sections per rat) of SN were immunostained with antibodies against tyrosine hydroxylase (TH). (B,E) SN of 6-OHDA/Veh group, (C,F) SN of 6-OHDA/CAb group, (D,G) SN of 6-OHDA/BAb group. The bottom photos (E-G) are higher magnifications of the cells in black rectangles of ipsilateral SN in the upper photos (B-D). Scale bar: 1 mm (B-D); scale bar: 50 μm (E-G). Arrows: neurons; arrowheads: fibers. (A) Stereological cell counts of total TH-ir neurons on the ipsilateral side of the SN are shown as a percentage of the cells on the contralateral side (n = 5/group, # P < 0.0001). All the results were obtained in a two-blinded procedure. No significant difference was found between the group treated with 6-OHDA/Veh and the group treated with 6-OHDA/CAb (P = 0.5108). Data are presented as mean ± S.E.M.CC BY · PubMed Central

Figure 3 Effects of BAb on microglial morphology and cell number in SN. Representative sections of SN in different groups were immunostained with antibodies against CD11b (a microglia marker) (D-I) and MHC II (a marker for activated microglia) (J-O) 21 days after 6-OHDA-injection. G-I and M-O are higher magnifications of the fields outlined by rectangles in D-F and J-L respectively. Scale bar: 500 μm in D-F and J-L; scale bar: 50 μm in G-I and M-O. Representative microglia in different stages (stage1-4) of CD11b immunostaining are shown in yellow circles (stage1: P1; stage2: P2; stage3: P3; stage4: P4), and a representative of stage 4 MHC II-ir microglia is shown in panel Q. Scale bar:10 μm in P1-P4 and Q. Microglia cell numbers and morphology were stereologically analyzed in each group. (A) Data represents average increase of CD11b-ir microglia cell number in ipsilateral SN as compared to contralateral SN (n = 5) ± S.E.M. #:P < 0.001. (B) Stereological quantification of each stage of CD11b-ir microglia is depicted as the average percentage distribution per group. # p < 0.001 compared to every other group. (C) Stereological quantification of stage 4 MHC II-ir cells throughout the SN from different experimental groups is shown in bar graph; n = 5, value = mean ± S.E.M. #: P < 0.001 significant difference compared to every other group.CC BY · PubMed Central

Figure 4 BAb regulates pro-inflammatory factor production in SN. Concentrations of TNF-α and IL-6 in SN were assayed using ELISA at 21 days post-6-OHDA injection. Values are shown as mean ± S.E.M. The concentrations of cytokines in the 6-OHDA/BAb co-treated group were significantly higher than those in the other groups. There was no significant difference between the 6-OHDA/CAb- and the 6-OHDA/Veh-treated groups. Data are representative of three individual experiments. # P < 0.001, significant difference compared to every other group.CC BY · PubMed Central

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PROTEIN MEASUREMENT WITH THE FOLIN PHENOL REAGENT
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Method
Staging of brain pathology related to sporadic Parkinson’s disease
Braak, H., Tredici, K. D., Rüb, U., de Vos, R. A. I., Jansen Steur, E. N. H., & Braak, E. (2003) · Neurobiology of Aging · doi:10.1016/s0197-4580(02)00065-9 · Cited by 10,777 · cited 1×
“Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world, and is characterized by dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) [1].”
Background
Microglia: a sensor for pathological events in the CNS
Kreutzberg, G. W. (1996) · Trends in Neurosciences · doi:10.1016/0166-2236(96)10049-7 · Cited by 4,396 · cited 7×
“Kyrkanides S, O’Banion MK, Whiteley PE, Daeschner JC, Olschowka JA: Enhanced glial activation and expression of specific CNS inflammationrelated molecules in aged versus young rats following cortical stab injury.”
BackgroundMethodInfluential
Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator
West, M. J., Slomianka, L., & Gundersen, H. J. G. (1991) · The Anatomical Record · doi:10.1002/ar.1092310411 · Cited by 2,994 · cited 1×
“Unbiased stereological estimates of DA (TH-positive cell) neuron numbers were performed using StereoInvestigator analysis software (MicroBrightField, Williston, VT), combined with a Nikon Eclipse E600 microscope, and the optical fractionator method according to previously published reports [42,43].”
Method
Reactive microglia are positive for HLA‐DR in the substantia nigra of Parkinson's and Alzheimer's disease brains
McGeer, P. L., Itagaki, S., Boyes, B. E., & McGeer, E. G. (1988) · Neurology · doi:10.1212/wnl.38.8.1285 · Cited by 2,990 · cited 2×
“Molecules related to neuroinflammation, such as tumor necrosis factor-alpha (TNF-a), IL-6, IL-1b, interferongamma (IFN-g), and superoxide, have been found colocalized with microglia in brain, and in cerebrospinal fluid and serum of PD patients as well [6,7,14-22].”
Background
Quantitative recording of rotational behavior in rats after 6-hydroxy-dopamine lesions of the nigrostriatal dopamine system
Ungerstedt, U., & Arbuthnott, G. W. (1970) · Brain Research · doi:10.1016/0006-8993(70)90187-3 · Cited by 1,995 · cited 1×
“Rotational behaviour was tested in rotometer bowls [47].”
Method
Neuroinflammation in Parkinson’s disease: A target for neuroprotection?
Hirsch, E. C., & Hunot, S. (2009) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70062-6 · Cited by 1,984 · cited 1×
“To further confirm a relationship between CD200CD200R signalling and neuroinflammation in PD, we assayed several molecules that would be secreted by activated microglia in the proinflammatory stage [10,55-59].”
Method
The role of inflammation in CNS injury and disease
Lucas, S., Rothwell, N. J., & Gibson, R. M. (2006) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706400 · Cited by 1,272 · cited 1×
“To further confirm a relationship between CD200CD200R signalling and neuroinflammation in PD, we assayed several molecules that would be secreted by activated microglia in the proinflammatory stage [10,55-59].”
Method
In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease
Gerhard, A., Pavese, N., Hotton, G., Turkheimer, F., Es, M., Hammers, A., Eggert, K., Oertel, W., Banati, R. B., & Brooks, D. J. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.08.002 · Cited by 1,200 · cited 1×
“Activated microglia are found in the SN of mesencephalon in the brain of PD patients [5-8] and of parkinsonian animal models [9-13].”
Background
Down-Regulation of the Macrophage Lineage Through Interaction with OX2 (CD200)
Hoek, R. M., Ruuls, S. R., Murphy, C. A., Wright, G. J., Goddard, R., Zurawski, S. M., Blom, B., Homola, M. E., Streit, W. J., Brown, M. H., et al. (2000) · Science · doi:10.1126/science.290.5497.1768 · Cited by 1,022 · cited 7×
“In addition, preventing CD200CD200R interactions with CD200R-blocking antibodies also induces augmented microglial activation in EAE rats [32,33].”
BackgroundInfluential

Show all 85 references

Sorted by citations

Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets
Gao, C., Jiang, J., Tan, Y., & Chen, S. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01588-0 · Cited by 1,616
“253 Besides, CB1 receptors are abundant in neurons, while CB2 receptors are primarily expressed in microglia in the brain.”
BackgroundSelf-citation
Microglia development and function
Nayak, D., Roth, T. L., & McGavern, D. B. (2014) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032713-120240 · Cited by 1,154
Neuroinflammation in Parkinson's disease and its potential as therapeutic target
Wang, Q., Liu, Y., & Zhou, J. (2015) · Translational Neurodegeneration · doi:10.1186/s40035-015-0042-0 · Cited by 884
“Likewise, dysfunction of CD200-CD200R signaling also increases the activation of microglia and exacerbates the degeneration of DA neurons in rat PD models [30, 31].”
Background
Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration
Perry, V. H., & Teeling, J. L. (2013) · Seminars in Immunopathology · doi:10.1007/s00281-013-0382-8 · Cited by 638
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“In rat PD models, both deficiency CX3CL1 or CX3CR1 as well as the dysfunction of CD200CD200R signaling have been shown to increase microglial activation and the degeneration of DA neurons (Wang et al., 2011; Zhang et al., 2011).”
Background

See all 154

Open Access
Zhang, S., Wang, X.-J., Tian, L.-P., Pan, J., Lu, G.-Q., Zhang, Y.-J., Ding, J., & Chen, S.-D. (2013)
The CD200R1 microglial inhibitory receptor as a therapeutic target in the MPTP model of Parkinson’s disease
Rabaneda‐Lombarte, N., Serratosa, J., Bové, J., Vila, M., Saura, J., & Solà, C. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02132-z · Cited by 33
CD200–CD200R Regulation of Microglia Activation in the Pathogenesis of Parkinson’s Disease
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Altered expression of the immunoregulatory ligand-receptor pair CD200-CD200R1 in the brain of Parkinson’s disease patients
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Impaired CD200-CD200R-mediated microglia silencing enhances midbrain dopaminergic neurodegeneration: roles of aging, superoxide, NADPH oxidase, and p38 MAPK
Wang, X.-J., Zhang, S., Yan, Z.-Q., Zhao, Y.-X., Zhou, H.-Y., Wang, Y., Lu, G.-Q., & Zhang, J.-D. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.01.032 · Cited by 108
Altered Regulation of CD200 Receptor in Monocyte-Derived Macrophages from Individuals with Parkinson’s Disease
Luo, X., Zhang, J.-J., Zhang, C., Liu, R., Zheng, L., Wang, X., Chen, S., & Ding, J. (2009) · Neurochemical Research · doi:10.1007/s11064-009-0094-6 · Cited by 42
Disease progression-dependent expression of CD200R1 and CX3CR1 in mouse models of Parkinson's disease
Wang, L., Liu, Y., Yan, S., Du, T., Fu, X., Gong, X., Zhou, X., Zhang, T., & Wang, X. (2020) · Aging and disease · doi:10.14336/ad.2019.0615 · Cited by 49
CD200 maintains the region‐specific phenotype of microglia in the midbrain and its role in Parkinson's disease
Wang, L., Gong, X., Liu, Y., Du, T., Zhang, Z., Zhang, T., & Wang, X. (2020) · Glia · doi:10.1002/glia.23811 · Cited by 15
Myeloid-specific blockade of notch signaling alleviates dopaminergic neurodegeneration in Parkinson’s disease by dominantly regulating resident microglia activation through NF-κB signaling
Liang, S.-Q., Li, P.-H., Hu, Y., Zhao, J., Shao, F.-Z., Kuang, F., Ren, K., Wei, T., Fan, F., Feng, L., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1193081 · Cited by 16
Role of inflammation in 6- hydroxydopamine model of Parkinson’s disease and its modulation by Peroxisome Proliferator Activated receptor gamma (PPAR-γ) agonist as a neuroprotective strategy
Sadeghian, M. (2008) · doi:10.25560/4400

Authors: Zhang, S., Wang, X.-J., Tian, L.-P., Pan, J., Lu, G.-Q., Zhang, Y.-J., Ding, J.-Q., & Chen, S.-D.
Affiliations: Shanghai Jiao Tong University (CN)
ORCID: Pan, Jing
Venue: Journal of Neuroinflammation
Publisher: Springer Science and Business Media LLC
Published: 2011-11-06
Volume: 8
Issue: 1
Pages: 154-154
ISSN: 1742-2094 (ISSN-L)
DOI: 10.1186/1742-2094-8-154
PMC: PMC3226566
OpenAlex: W2033271712
Cited by: 154
References: 85
Citations by year: 2026: 3 · 2025: 7 · 2024: 13 · 2023: 12 · 2022: 8 · 2021: 11 · 2020: 10 · 2019: 13 · 2018: 10 · 2017: 8 · 2016: 10 · 2015: 8 · 2014: 16 · 2013: 16 · 2012: 8
FWCI: 7.24
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: Journal of Neuroinflammation (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
Keywords: Parkinson's disease, microglial activation, dopaminergic neuron loss, 6-hydroxydopamine lesion, substantia nigra, neuroinflammation, inflammatory cytokines, monoamine levels, motor impairment, striatum, neuroprotection, rat model
MeSH terms: Animals, Behavior, Animal, Disease Models, Animal, Dopamine, Humans, Male, Nerve Degeneration, Receptors, Immunologic, Antigens, CD, Oxidopamine, Rats, Sprague-Dawley, Microglia, Antibodies, Blocking, Parkinsonian Disorders, Rats, Dopaminergic Neurons

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CD200-CD200R dysfunction exacerbates microglial activation and dopaminergic neurodegeneration in a rat model of Parkinson's disease

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