Abstract
Objectives: Lung disease is the leading cause of mortality in cystic fibrosis(CF), a disorder caused by mutations in the CFTR gene, and is characterisedby a repetitive circle of infection and inflammation. Among the pathogenicbacteria found in CF airway, the multidrug-resistant Mycobacteriumabscessus (Mabs) is associated with accelerated inflammatory lungdamage and is often refractory to antibiotic therapies. Therefore, weexamined whether curcumin, an activator of the transcription factor NRF2,might provide a beneficial effect against Mabs infection in the context of CF.Methods: Herein, using CFTR-depleted zebrafish larvae as an innovativemodel of inflammation and infection, we sought to determine the effects ofcurcumin on host immune responses to Mabs infections in CF condition.Results: Firstly, we show that treatment with curcumin exerts anti-inflammatory effects in neutrophilic inflammation induced by Mabsinfection in CFTR-depleted zebrafish. As a consequence, the reducednumber of neutrophils at infected sites prevents tissue damage. Our findings show that curcumin alleviates Mabs-induced inflammatorydamage by restoring NRF2 activity in CF animals. Next, while curcuminhas no direct antibacterial activity against Mabs, our results indicated thatcurcumin improves the control of Mabs infections in CF zebrafish,correlating with reduced larval mortality and lower bacterial loads. Inparticular, we found that NRF2 activation with curcumin enhances Mabskilling in macrophages in vivo, demonstrating that NFR2 is instrumental toefficiently restrict the intracellular growth of Mabs, thereby preventingbacterial spread and more severe infection in CF.Conclusion: Our findings bring new understanding of the immune-targeted action of curcumin, and show that therapeutic strategies tonormalise NRF2 activity might simultaneously enhance bacterial killingand promote inflammation resolution thus prevent infectious andinflammatory lung damage in CF.