DJ-1 modulates Nrf2-mediated MRP1 expression by activating Wnt3a/β-catenin signalling in A549 cells exposed to cigarette smoke extract and LPS

Jian Zhou, Chuanzong Qi, Xin Fang, Zihao Wang, Shuyi Zhang, Dalang Li, Jue Song
Life Sciences 2021 January 18, : 119089

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an inflammatory disease characterized by airway obstruction and abnormal inflammatory responses. Multidrug resistance-related protein 1 (MRP1) can reduce lung inflammation and damage by excreting various toxic exogenous substances and certain pro-inflammatory molecules.

AIMS: We studied whether DJ-1 modulates nuclear factor erythroid 2-related factor 2 (Nrf2) by activating the Wnt3a/β-catenin signalling pathway to further regulate MRP1 expression and pulmonary antioxidant defences in alveolar epithelial (A549) cells treated with smoke extract (CSE) and lipopolysaccharide (LPS).

MAIN METHODS: Marker expression was studied by western blot analysis, quantitative real-time PCR and immunofluorescence staining of A549 cells.

KEY FINDINGS: A549 cells exposed to CSE and LPS showed downregulation of DJ-1, Wnt3a, MRP1 and haem oxygenase-1 (HO-1) and upregulation of inflammatory factors. Additionally, Nrf2 protein levels were significantly decreased, while there was no change in Nrf2 mRNA levels. Overexpression of DJ-1 and Wnt3a activated Nrf2 signalling, increased MRP1 and HO-1 levels and decreased IL-6 protein expression, while knockdown of DJ-1 and Wnt3a had the opposite effects. Furthermore, DJ-1 overexpression and DJ-1 knockdown increased and decreased, respectively, the levels of Wnt3a and β-catenin. Interestingly, Nrf2 and Wnt3a deficiency reduced the protective effects of Wnt3a and DJ-1, respectively, in A549 cells. However, the levels of DJ-1 and Wnt3a were not altered by Wnt3a and Nrf2 deletion, respectively.

SIGNIFICANCE: In A549 cells treated with CSE and LPS, DJ-1 regulates Nrf2-mediated MRP1 expression and antioxidant defences by activating the Wnt3a/β-catenin signalling pathway. These findings may provide potential therapeutic targets for COPD intervention.

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