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Alpha synuclein deficiency increases CD4+ T-cells pro-inflammatory profile in a Nurr1-dependent manner

Trudler, D;Levy-Barazany, H;Nash, Y;Samuel, L;Sharon, R;Frenkel, D;

It has been suggested that extracellular alpha synuclein (Syn) can mediate neuroinflammation in Parkinson’s disease, and that Syn affects B-cell maturation. However, the function of Syn in T cells is poorly understood. We hypothesized that Syn can affect CD4+ T-cell proliferation and activity. We found that Syn deficiency exacerbates disease progression in 8 weeks old C57BL6/J EAE-induced mice, and that Syn-deficient CD4+ T cells have increased pro-inflammatory response to myelin antigen relative to wild-type cells, as measured by cytokine secretion of interleukin IL-17 and interferon gamma (IFN). Furthermore, expression of Syn on a background of Syn knockout mitigates the inflammatory responses in CD4+ T cells. We discovered that elevated levels of Nurr1, a transcription factor belonging to the orphan nuclear receptor family, are associated with the pro-inflammatory profile of Syn-deficient CD4+ T cells. In addition, we demonstrated that silencing of Nurr1 expression using an siRNA reduces IL-17 levels and increases the levels of IL-10, an anti-inflammatory cytokine. Study of Syn-mediated cellular pathways in CD4+ T cells may provide useful insights into the development of pro-inflammatory responses in immunity, providing future avenues for therapeutic intervention. 2019 International Society for Neurochemistry.