|Journal of Neuroinflammation|
|Neuroprotective efects of ex vivo-expanded regulatory T cells on trimethyltin-induced neurodegeneration in mice|
Background: Trimethyltin (TMT) is a potent neurotoxicant that leads to hippocampal neurodegeneration. Regula‑ tory T cells (Tregs) play an important role in maintaining the immune balance in the central nervous system (CNS), but their activities are impaired in neurodegenerative diseases. In this study, we aimed to determine whether adoptive transfer of Tregs, as a living drug, ameliorates hippocampal neurodegeneration in TMT-intoxicated mice.
Methods: CD4+CD25+ Tregs were expanded in vitro and adoptively transferred to TMT-treated mice. First, we explored the efects of Tregs on behavioral defcits using the Morris water maze and elevated plus maze tests. Bio‑ markers related to memory formation, such as cAMP response element-binding protein (CREB), protein kinase C (PKC), neuronal nuclear protein (NeuN), nerve growth factor (NGF), and ionized calcium binding adaptor molecule 1 (Iba1) in the hippocampus were examined by immunohistochemistry after killing the mouse. To investigate the neuroin‑ fammatory responses, the polarization status of microglia was examined in vivo and in vitro using real-time reverse transcription polymerase chain reaction (rtPCR) and Enzyme-linked immunosorbent assay (ELISA). Additionally, the inhibitory efects of Tregs on TMT-induced microglial activation were examined using time-lapse live imaging in vitro with an activation-specifc fuorescence probe, CDr20.
Results: Adoptive transfer of Tregs improved spatial learning and memory functions and reduced anxiety in TMTintoxicated mice. Additionally, adoptive transfer of Tregs reduced neuronal loss and recovered the expression of neu‑ rogenesis enhancing molecules in the hippocampi of TMT-intoxicated mice. In particular, Tregs inhibited microglial activation and pro-infammatory cytokine release in the hippocampi of TMT-intoxicated mice. The inhibitory efects of TMT were also confrmed via in vitro live time-lapse imaging in a Treg/microglia co-culture system.
Conclusions: These data suggest that adoptive transfer of Tregs ameliorates disease progression in TMT-induced neurodegeneration by promoting neurogenesis and modulating microglial activation and polarization.
Keywords: Regulatory T cells, Hippocampal neurodegeneration, Trimethyltin, Cell therapy, Microglia