title: Complex Changes in the Innate and Adaptive Immunity Accompany Progressive Degeneration of the Nigrostriatal Pathway Induced by Intrastriatal Injection of 6-Hydroxydopamine in the Rat.
abstract: We investigated changes in innate and adaptive immunity paralleling the progressive nigrostriatal damage occurring in a neurotoxic model of Parkinson's disease (PD) based on unilateral infusion of 6-hydroxydopamine (6-OHDA) into the rat striatum. A time-course analysis was conducted to assess changes in morphology (activation) and cell density of microglia and astrocytes, microglia polarization (M1 vs. M2 phenotype), lymphocyte infiltration in the lesioned substantia nigra pars compacta (SNc), and modifications of CD8+ and subsets of CD4+ T cell in peripheral blood accompanying nigrostriatal degeneration. Confirming previous results, we observed slightly different profiles of activation for astrocytes and microglia paralleling nigral neuronal loss. For astrocytes, morphological changes and cell density increases were mostly evident at the latest time points (14 and 28 days post-surgery), while moderate microglia activation was present since the earliest time point. For the first time, in this model, we described the time-dependent profile of microglia polarization. Activated microglia clearly expressed the M2 phenotype in the earlier phase of the experiment, before cell death became manifest, gradually shifting to the M1 phenotype as SNc cell death started. In parallel, a reduction in the percentage of circulating CD4+ T regulatory (Treg) cells, starting as early as day 3 post-6-OHDA injection, was detected in 6-OHDA-injected rats. Our data show that nigrostriatal degeneration is associated with complex changes in central and peripheral immunity. Microglia activation and polarization, Treg cells, and the factors involved in their cross-talk should be further investigated as targets for the development of therapeutic strategies for disease modification in PD.
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, C. Mondino National Neurological Institute, Via Mondino, 2, 27100, Pavia, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Ambrosi
authors.affiliation: Center of Research in Medical Pharmacology, University of Insubria, Varese, Italy.
authors.forename: Natasa
authors.initials: N
authors.lastname: Kustrimovic
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, C. Mondino National Neurological Institute, Via Mondino, 2, 27100, Pavia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Siani
authors.affiliation: Center of Research in Medical Pharmacology, University of Insubria, Varese, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Rasini
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, C. Mondino National Neurological Institute, Via Mondino, 2, 27100, Pavia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Cerri
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, C. Mondino National Neurological Institute, Via Mondino, 2, 27100, Pavia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ghezzi
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, C. Mondino National Neurological Institute, Via Mondino, 2, 27100, Pavia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Dicorato
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, C. Mondino National Neurological Institute, Via Mondino, 2, 27100, Pavia, Italy.
authors.forename: Sofia
authors.initials: S
authors.lastname: Caputo
authors.affiliation: Center of Research in Medical Pharmacology, University of Insubria, Varese, Italy.
authors.forename: Franca
authors.initials: F
authors.lastname: Marino
authors.affiliation: Center of Research in Medical Pharmacology, University of Insubria, Varese, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Cosentino
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, C. Mondino National Neurological Institute, Via Mondino, 2, 27100, Pavia, Italy. fabio.blandini@mondino.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Blandini
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects*; D000818:Animals; D015703:Antigens, CD; D001253:Astrocytes / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004660:Encephalitis / Q000139:chemically induced*; D005434:Flow Cytometry; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D016627:Oxidopamine / Q000633:toxicity*; D010300:Parkinson Disease / Q000150:complications / Q000209:etiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology*; D013565:Sympatholytics / Q000633:toxicity*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D005904:Glial Fibrillary Acidic Protein; D013565:Sympatholytics; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase
keywords: 6-OHDA; Astrocytes; Microglia; Parkinson’s disease; Rat; T regulatory cells