Tyrosine: A Key Neurotransmitter in Selective Serotonin Reuptake Inhibitor Treatment for Chronic Restraint Stress-Induced Reduction of Intestinal Innate Lymphoid Cell Type 3 Cells

Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants. Given the prevalence of depression and its associated immune dysregulation, understanding the role of SSRIs in these processes is crucial. This study aims to explore the effects of SSRIs on chronic restraint stress (CRS)-induced depressive-like behaviors and immune functions. Mice subjected to CRS were administered citalopram (CITA) during the modeling period, followed by behavioral assessments. Histological examination and flow cytometry were used to analyze the immune status and cells of the spleen and intestine. Cellular experiments were performed for verification. We found that CITA treatment significantly alleviated weight loss and depression-like behaviors in CRS mice. Moreover, CITA ameliorated CRS-induced immune dysregulation in the spleen and reversed the decreased villus/crypt ratio in the ileum. Although CITA had minimal impact on restoring intraepithelial lymphocytes after CRS, it significantly reversed the reduction in innate lymphoid cell type 3 (ILC3) levels. Notably, although levels of the serotonin precursor 5-hydroxytryptophan remained unchanged in the ileum, tyrosine levels significantly increased after CRS and were further reduced by CITA treatment. Treatment of primary ILC3s with 4-ethylphenol, a tyrosine metabolite, decreased ILC3 cells and their related IL-7 levels, suggesting that tyrosine may be a key neurotransmitter regulating ILC3 levels through CITA. Hence, CITA effectively ameliorates CRS-induced depressive-like behaviors and immune dysfunctions in the spleen and intestine. Tyrosine is a crucial neurotransmitter in CITA treatment for regulating depression-related intestinal immune disorders.