327 - Thioredoxin-interacting protein, a potential pharmacological target for the treatment of depression

Abstract

Chronic stress is a key contributor to depression. Studies show that oxidative stress and inflammation are increased in rodents exposed to chronic stress and in patients with depression. Thioredoxin as a redox protein can reduce protein cysteine oxidative modification and inhibit apoptosis signal-regulating kinase 1 (ASK1) stress and inflammatory pathway. Therefore thioredoxin plays an important role in defense against oxidative stress and inflammation. Thioredoxin-interacting protein (Txnip) can inhibit thioredoxin. The purpose of this study was to investigate thioredoxin and Txnip in brain of mice exposed to chronic unpredictable stress (CUS) and in postmortem brain of patient with depression. We found that mice exposed to CUS displayed depressive-like behavior including decreased exploration, increased anhedonia and increased despair. Although CUS had no effect on thioredoxin levels, it increased Txnip levels in mouse hippocampus and frontal cortex. Further Txnip levels were upregulated by chronic treatment with stress hormone corticosterone (CORT) in cultured neuronal cells and in postmortem anterior cingulate of patient with depression. Txnip not only inhibits Trx, enhancing cysteine oxidative modification and ASK1 activation; but also binds to nod-like receptor protein 3 (NLRP3), facilitating NLRP3 inflammasome forming. We found that CUS increased protein sulfenylation and nitrosylation, and ASK1 phosphorylation in mouse brain. Knocking out Txnip using CRISPR/Cas9 technology blocked chronic CORT treatment-increased sulfenylation and nitrosylation in cultured neuronal cells. We also found that CUS and CORT treatment increased Txnip-NLRP3 binding in mouse brain and cultured microglia. Our results suggest that chronic stress may upregulate Txnip, enhancing Txnip binding to Trx, which inhibit Trx reducing activity, subsequently promoting cysteine oxidative modification; and inhibit Trx binding to ASK1, facilitating ASK1 phosphorylation. CUS-upregulated Txnip may also enhance NLRP3-mediated inflammatory signaling. Because chronic stress is a major risk for depression, Txnip may be a novel potential target for the treatment of depression.