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Glial signaling mechanisms in the progression of neuroinflammatory injury




Popichak, Katriana A., author
Tjalkens, Ronald B., advisor
Bouma, Gerrit J., committee member
Goodrich, Laurie R., committee member
Legare, Marie E., committee member
McLean, Jennifer L., committee member

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The response of glial cells to foreign and endogenous stress signals is extensive. As a result, release of inflammatory factors as means of cellular communication and innate immune function, or neuroinflammation, can contribute to neurodegeneration and increased activation of surrounding glia, often associated with Parkinson's disease (PD). The identification of glial activation as an early event in the progression of neurodegenerative disease that precedes neuronal cell death presents an opportunity for better diagnostic markers, as well as new pathways that could be targeted therapeutically. The transcription factor, Nuclear Factor-kappa B (NF-κB), regulates the expression of multiple neuroinflammatory cytokines and chemokines in activated glial cells but the signaling factors modulating glial-glial and glial-neuronal signaling during neurotoxic injury are poorly understood. Thus, inhibition of NF-κB signaling in glial cells could be a promising therapeutic strategy for the prevention of neuroinflammatory injury. Recently, it was found that selected orphan nuclear receptors in the NR4A family (nerve growth factor-induced-β/NGFI-β), including NR4A1 (Nur77) and NR4A2 (Nurr1), can inhibit the inflammatory effects of NF-κB but there are no approved drugs that target these receptors. In the current studies, we utilized several experimental approaches to target neuroinflammation in cellular models of PD and manganese neurotoxicity in primary glia and in animal models. One of these studies demonstrated that a novel ligand of NR4A1 and NR4A2, 1,1-bis (3'-indolyl) -1-(p-methoxyphenyl) methane (C-DIM5), suppressed NF-κB-dependent inflammatory gene expression in astrocytes following treatment with 1-methyl-4-phenyl-1, 2, 3,6-tetrahydropyridine (MPTP) and the inflammatory cytokines, IFN-γ and TNF-α. These data were further supported by previous studies from our laboratory, which examined efficacy of multiple C-DIM compounds in PD animal and cellular models, including one (C-DIM12) identified as a modulator of Nurr1 activity that also inhibited NF-kB-dependent gene expression in glial cells. Collectively, these data demonstrate that NR4A1/Nur77 and NR4A2/Nurr1 dynamically regulated inflammatory gene expression in glia by modulating the transcriptional activity of NF-κB. An additional study examined the role of NF-κB in manganese (Mn)-induced neurotoxicity by exposing purified microglia, astrocytes (from both wild-type and an astrocyte- specific NF-kB (IKK2) knock-out (KO) mouse) and mixed glial cultures to varying Mn concentrations and then treated neurons with the conditioned media (GCM) of each cell type. In doing so, we showed that mixed glial cultures exposed to Mn enhanced glial activation and neuronal death compared to microglia, wild type astrocytes or IKK2-knockout astrocytes alone or in mixed cultures suggesting that astrocytes are a critical mediator of Mn neurotoxicity through enhanced expression of inflammatory cytokines and chemokines, including those most associated with reactive phenotype such as C3 and CCL2. Thus, these studies elucidate key mechanisms associated with neuroinflammation and present potential therapeutic targets in glial cells that regulate the progression of neuroinflammatory injury.


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