title: Attenuation of microglial RANTES by NEMO-binding domain peptide inhibits the infiltration of CD8(+) T cells in the nigra of hemiparkinsonian monkey.
abstract: Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Despite intense investigations, little is known about its pathological mediators. Here, we report the marked upregulation of RANTES (regulated on activation, normal T cell expressed and secreted) and eotaxin, chemokines that are involved in T cell trafficking, in the serum of hemiparkinsonian monkeys. Interestingly, 1-methyl-4-phenylpyridinium (MPP(+)), a Parkinsonian toxin, increased the expression of RANTES and eotaxin in mouse microglial cells. The presence of NF-κB binding sites in promoters of RANTES and eotaxin and down-regulation of these genes by NEMO-binding domain (NBD) peptide, selective inhibitor of induced NF-κB activation, in MPP(+)-stimulated microglial cells suggest that the activation of NF-κB plays an important role in the upregulation of these two chemokines. Consistently, serum enzyme-linked immuno assay (ELISA) and nigral immunohistochemistry further confirmed that these chemokines were strongly upregulated in MPTP-induced hemiparkinsonian monkeys and that treatment with NBD peptides effectively inhibited the level of these chemokines. Furthermore, the microglial upregulation of RANTES in the nigra of hemiparkinsonian monkeys could be involved in the altered adaptive immune response in the brain as we observed greater infiltration of CD8(+) T cells around the perivascular niche and deep brain parenchyma of hemiparkinsonian monkeys as compared to control. The treatment of hemiparkinsonian monkeys with NBD peptides decreased the microglial expression of RANTES and attenuated the infiltration of CD8(+) T cells in nigra. These results indicate the possible involvement of chemokine-dependent adaptive immune response in Parkinsonism.
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States.
authors.forename: A
authors.initials: A
authors.lastname: Roy
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States.
authors.forename: S
authors.initials: S
authors.lastname: Mondal
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States.
authors.forename: J H
authors.initials: JH
authors.lastname: Kordower
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States; Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, 820 South Damen Avenue, Chicago, IL, United States. Electronic address: kalipada_pahan@rush.edu.
authors.forename: K
authors.initials: K
authors.lastname: Pahan
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D023081:CCAAT-Binding Factor / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D054413:Chemokine CCL11 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D008253:Macaca mulatta; D051379:Mice; D008840:Microfilament Proteins; D017628:Microglia / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000473:pathology*; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology; D013378:Substantia Nigra / Q000473:pathology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C112986:AIF1 protein, human; D015703:Antigens, CD; D023081:CCAAT-Binding Factor; D002135:Calcium-Binding Proteins; D054413:Chemokine CCL11; D018946:Chemokine CCL5; D016207:Cytokines; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; C467063:NBD peptide, mouse; C492062:Nfyb protein, mouse; D010455:Peptides; D014446:Tyrosine 3-Monooxygenase
keywords: Parkinson’s disease; RANTES; T cell infiltration; hemiparkinsonian monkeys; microglia; neuroinflammation