Oxidative stress triggers Itch-mediated TXNIP degradation and NF-κB activation promoting chronic obstructive pulmonary disease

BACKGROUND: Chronic inflammatory lung diseases, including chronic obstructive pulmonary disease (COPD), are characterized by pulmonary structural changes, narrowing of the small airways, and destruction of the lung parenchyma caused by prolonged inflammation. Sustained inflammation mediated by macrophages is considered to play a critical role in COPD pathogenesis, while the inductive mechanisms of persistent inflammation remain unclear. METHODS: In vitro, RAW264.7 cells were treated with cigarette smoke extract (CSE), hydrogen peroxide, and 12-O-tetradecanoylphorbol-13-acetate. Loss-of-function assays were performed using MAPK inhibitors and Itch-specific knockdown. In vivo, lung tissues from mice exposed to whole-body cigarette smoke (CS) for 12 weeks, as well as clinical samples from healthy non-smokers, a healthy smoker, and COPD patients, were analyzed. RESULTS: Our findings demonstrated that thioredoxin-interacting protein (TXNIP) participates in CS-induced NF-κB activation in macrophages, which may contribute to pulmonary inflammation. CSE markedly inhibited TXNIP expression in RAW264.7 cells through MAPK-dependent regulation, accompanied by the induction of iNOS/NO and COX-2. The decrease in TXNIP was also detected in lung tissues and macrophages obtained from smoking mice, while higher NF-κB activation and lung inflammation occurred simultaneously. Additionally, CS-induced oxidative stress triggered MAPK-dependent proteasomal degradation of TXNIP, leading to subsequent NF-κB activation. The expression of E3 ligase Itch was elevated in smoking mouse lungs and in hydrogen peroxide-stimulated cells, whereas specific silencing Itch significantly attenuated TXNIP degradation as well as NF-κB activation. Moreover, Itch expression was increased in lung tissues, whereas TXNIP was markedly reduced in lung tissues, bronchoalveolar lavage fluid cells, and peripheral blood mononuclear cells from patients with COPD. CONCLUSION: Accordingly, CS-induced oxidative stress promotes Itch-mediated TXNIP degradation, leading to NF-κB-driven inflammation in macrophages and potentially contributing to COPD pathogenesis.