Loss of lung WWOX expression causes neutrophilic inflammation

Area of Science:

• Pulmonary medicine
• Molecular biology
• Oncology

Background:

• The WW domain-containing oxidoreductase (WWOX) tumor suppressor interacts with key inflammation and cancer signaling pathways.
• Genotoxic exposures can downregulate WWOX, implicating it in lung pathobiology.

Purpose of the Study:

• To investigate the role of WWOX in lung inflammatory responses.
• To elucidate the molecular mechanisms linking WWOX to neutrophil recruitment in the lungs.

Main Methods:

• WWOX expression was knocked down in mouse lungs and human alveolar epithelial cells.
• Neutrophil influx, vascular leak, and inflammatory cytokine production were assessed.
• Interactions between WWOX and c-Jun, and the role of JNK signaling, were examined.

Main Results:

• WWOX knockdown in mice led to neutrophil influx, vascular leak, and inflammatory cytokine release.
• Loss of WWOX in human alveolar cells increased neutrophil chemotaxis, mediated by c-Jun and IL-8.
• WWOX directly interacts with c-Jun, and its absence promotes c-Jun nuclear translocation.
• Inhibition of JNK abrogated WWOX knockdown-induced neutrophil influx in mice.

Conclusions:

• WWOX plays a critical role in suppressing pulmonary neutrophil influx.
• A novel mechanism involving WWOX, c-Jun, and JNK signaling in lung inflammation is identified.
• These findings offer potential therapeutic strategies for lung inflammatory diseases.