Targeting TNIP1 as a new therapeutic avenue for major depressive disorder

Abstract

TNFAIP3-interacting protein 1 (TNIP1) is a polyubiquitin-binding protein that functions as a negative regulator of NF-κB pathway and alleviates inflammation, but little is known about its role in major depressive disorder (MDD). After discovering an elevated TNIP1 expression in monocytes from individuals with MDD after antidepressant treatment, our analyses further uncovered a significant rise in TNIP1 mRNA expression among patients experiencing remission after antidepressant treatment, particularly in those who received duloxetine. We aimed to explore the potential of TNIP1 as a potential therapeutic target for treatment of MDD. In vitro cell line studies showed that TNIP1 is induced by duloxetine to suppress TNF-α through increasing PPAR-γ receptor expression as anti-inflammatory effects and combined treatment of PPAR-γ agonist pioglitazone and duloxetine exerts synergistic effects on TNIP1 expression. Furthermore, an animal study also demonstrated duloxetine-induced TNIP1 expression in CA3 region of hippocampus, suggesting the TNIP1 expression is up-regulated by antidepressants. We further investigated the potential effect of TNIP1 as a therapeutic target in alleviating depressive-like behavior in chronic mild stress model C57BL/6 mice overexpressing TNIP1 in the hippocampal CA3 region. The results showed that overexpression of TNIP1 in the CA3 region of the hippocampus through cerebral microdialysis significantly reduces depressive-like behavior in mice. In contrast, TNIP1 knockdown in the CA3 region of the hippocampus causes depressive-like behavior and Duloxetine failed to rescue depressive-like behavior in TNIP1-knockdown mice. Together, these data suggest targeting TNIP1 as a novel therapeutic regiment may provide a promising future for pharmacological development of antidepressants in remitting MDD.

Keywords: Antidepressants; Duloxetine; Hippocampus; Neuroinflammation; PPAR-γ.