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Abstract or Description
Parkinson's disease (PD) is a neurodegenerative movement disorder in which symptoms derive from deficits in dopamine neurotransmitter levels secondary to loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) associated with misfolding and accumulation of α−synuclein. Neuroinflammation via microglia and T effector cells (Teffs) contribute to dopaminergic neuronal cell death. Recognition of cytokine profiles of pro-inflammatory microglia is not well understood and serve as potential therapeutic targets to reduce neuroinflammation. Recent studies demonstrated a novel Th17.1 Teff clonotype increases neurotoxicity. The aim of this study was to demonstrate in vitro cytokine responses by BV-2 microglia induced by Th1, Th17, and Th17.1 clonotypes to assess neuroinflammation mechanisms in PD. Cytokine responses by BV-2 microglia co-cultured with activated Teff clonotypes were analyzed using a cytokine membrane array. Co-culture with Teffs led to significant increases in the majority of cytokine responses from BV-2 microglia compared to control. Cross group analysis relative expression demonstrated variation in cytokine profiles produced between microglia treated with different Teff clonotypes, especially with regard to IFNγ, MIG, MIP-1α, TIMP-1, RANTES, SDF-1, and IL-12 p40/p70. Ingenuity Pathway Analysis (IPA) of cytokines displaying significant relative expression levels for each Teff clonotype showed Th1- and Th17- treated BV-2 microglia demonstrated pathways related to cellular movement, hematological development and function, and immune trafficking while Th17.1-treated microglia upregulated pathways related to disorders of connective tissues, inflammation, and organismal injury. In conclusion, Th1, Th17, and Th17.1 Teffs treatment of BV-2 microglia led to upregulation of most pro-inflammatory cytokines and pathways. However, specific Teff clonotype culture with BV-2 microglia displayed different cytokine profile responses through varying relative expression profiles with significant differences related to IFNγ, MIG, MIP-1α, TIMP-1, RANTES, SDF-1, and IL12 p40/p70 delineating alternative inflammatory pathways. These results provide relevant targets for strategies to attenuate neuroinflammation and protect dopaminergic neurons in PD.
Selko, Sean C.; Wilshusen, Rebecca A.; Olson, Katherine E.; and Mosley, R. Lee, "Differential Microglial Responses Induced by N-a-Synuclein-Specific Effector T Cell Clones" (2021). EMET Projects. 6.