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

Abstract

It has been suggested that extracellular alpha synuclein (αSyn) can mediate neuroinflammation in Parkinson’s disease, and that αSyn affects B‐cell maturation. However, the function of αSyn in T cells is poorly understood. We hypothesized that αSyn can affect CD4+ T‐cell proliferation and activity. We found that αSyn deficiency exacerbates disease progression in 8 weeks old C57BL6/J EAE‐induced mice, and that αSyn‐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. Furthermore, expression of αSyn on a background of αSyn 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 αSyn‐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 αSyn‐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. image

<p>NR4A2 Exacerbates Cerebral Ischemic Brain Injury via Modulating microRNA-652/Mul1 Pathway</p>

“…Interestingly, silencing of NR4A2 expression with siRNA downregulated IL-17 expression and upregulated the expression of IL-10, an anti-inflammatory factor. 33 Similarly, NR4A2 protected dopaminergic neurons against neuroinflammation insults by constricting the release of neurotoxic mediators by microglia, 34 while its role in regulating inflammation in ischemic stroke remains largely unknown. Therefore, our future attention may place it.…”

Aging exacerbates the brain inflammatory micro-environment contributing to α-synuclein pathology and functional deficits in a mouse model of DLB/PD

“…Moreover, recent studies suggest that ɑ-syn might trigger neurodegeneration through nonamyloid mechanisms [71]. Loss of function might be of interest for explaining immune system dysregulation since previous studies have shown that in ɑ-syn knockout mice there are alterations in the maturation of T and B cells [72][73][74]. Future studies will need to further explore these alternative mechanisms.…”