Paeonol alleviates PD-1 deficiency-induced anxiety-like behaviors through reversing the neurotransmitter metabolic disorders in spleen-brain axis.

BACKGROUND

Anxiety are frequently observed in patients with programmed cell death-1 (PD-1) blockade therapy, which is related with the overactivation of the immune system. Paeonol was described to regulate immune function and relieve mood symptoms, but no study focused on its mechanism on the emotional disorders caused by PD-L1/PD-1 blockade therapy.

PURPOSE: With Pdcd1-/- mice, we aim to evaluate the paeonol's anxiolytic effect and focus on the mechanism about the neurotransmitter metabolic shifts caused by T cells overactivation in peripheral immune organs.

METHODS

On the basis of the behavioral tests, we firstly quantified the contents of key neurotransmitters and their precursors in two brain regions and in spleen and lymph nodes of Pdcd1-/-mice. Then, we used flow cytometry with Treg suppression assay to explore paeonol's effects on CD4+T-cell function. Finally, molecular-docking were performed between paeonol and the forkhead box protein 3 (Foxp3) to predict the putative targets.

RESULTS

In Pdcd1-/- mice, the inhibitory effect of Tregs on CD4+T cells was diminished, resulting in the upregulation of CD44high in spleen. This hyperactivity of CD4+T cells caused the spleen to excessively accumulate tyrosine and tryptophan, which led to decreased levels of dopamine and 5-hydroxytryptamine and ultimately triggered anxiety-like behaviors. These abnormal changes could be alleviated through intervention with paeonol and the molecular docking suggested paeonol had a good binding with Foxp3.

CONCLUSION

Paeonol could alleviate anxiety-like behaviors by enhancing the Treg function through Foxp3 in the spleen, thereby correcting the neurotransmitter metabolic disorders in spleen-brain axis in Pdcd1-/-.