BACKGROUND

Neuroinflammation is a vital pathogenic mechanism for neurodegenerative diseases such as Alzheimer's, schizophrenia, and age-related cognitive decline. Regulatory T cells (Tregs) exhibit potent anti-inflammatory properties and can modulate neurodegenerative diseases arising from central nervous system inflammatory responses. However, the role of Tregs in neuroinflammation-related cognitive dysfunction remains unclear. It is highly plausible that Htr7 Tregs expressing unique genes associated with the nervous system, including the Htr7 gene encoding the serotonin receptor 5-HT, play a pivotal role.

METHODS

Mice were given a tryptophan-rich diet (with a tryptophan content of 0.6%) or a normal diet (with a tryptophan content of 0.16%). The neuroinflammation-mediated cognitive dysfunction model was established by intracerebroventricular injection of lipopolysaccharide (LPS) in 8-week-old C57BL/6J mice. The activation and infiltration of Tregs were measured using flow cytometry. Primary Tregs were cocultured separately with primary CD8 T cells and primary microglia for in vitro validation of the impact of 5-HT and 5-HT receptor on Tregs. Prior to their transfer into recombination activating gene 1 (Rag1) mice, Tregs were ex vivo transfected with lentivirus to knock down the expression of Htr7.

RESULTS

In this study, the tryptophan-rich diet was found to reverse LPS-induced cognitive impairment and reduce the levels of 5-HT in peripheral blood. The tryptophan-rich diet led to increased levels of 5-HT in peripheral blood, which in turn promoted the proliferation and activation of Htr7 Tregs. Additionally, the tryptophan-rich diet was also shown to attenuate LPS-mediated neuroinflammation by activating Htr7 Tregs. Furthermore, 5-HT and 5-HT receptor were found to enhance the immunosuppressive effect of Tregs on CD8 T cells and microglia. In Rag1 mice, Htr7 Tregs were shown to alleviate LPS-induced neuroinflammation and cognitive impairment.

CONCLUSIONS

Our research revealed the ability of Htr7 Tregs to mitigate neuroinflammation and prevent neuronal damage by suppressing the infiltration of CD8 T cells into the brain and excessive activation of microglia, thereby ameliorating LPS-induced cognitive impairment. These insights may offer novel therapeutic targets involving Tregs for neuroinflammation and cognitive impairment.