Tryptophan-rich diet and its effects on Htr7+ Tregs in alleviating neuroinflammation and cognitive impairment induced by lipopolysaccharide.

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-HT₇, 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-HT₇ 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-HT₇ 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.