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
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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.
KeywordsParkinson’s disease 6-OHDA Rat Microglia Astrocytes T regulatory cells
This study was supported by a grant from Fondazione CARIPLO to Marco Cosentino and Fabio Blandini (Project 2011-0504: Dopaminergic modulation of CD4+ T lymphocytes: relevance for neurodegeneration and neuroprotection in Parkinson’s disease—the dopaminergic neuro-immune connection). Natasa Kustrimovic (postdoc fellow) and Cristina Ghezzi (lab technician) appointments were supported by the grant. We would like to acknowledge Dr. Marco Gnesi for performing the statistical analysis of data and correlations. The skillful technical assistance of Dr. Emanuela Rasini (Center for Research in Medical Pharmacology, University of Insubria) in the development and validation of flow cytometric assays as well as in data analysis is also gratefully acknowledged.
FB, MC, and FM conceived and designed the study. GA, NK, FS, CG, SC, SC, GD and ER acquired data. GA, NK, FS, MC, and FB analyzed and interpreted data. All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved and declare to have confidence in the integrity of the contributions of their co-authors.
Compliance with Ethical Standards
The authors declare that they have no competing financial interests.
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