Quercetin negatively regulates IL-1β production inPseudomonas aeruginosa-infected human macrophages through the inhibition of MAPK/NLRP3 inflammasome pathways

Pseudomonas aeruginosaremains a leading cause of nosocomial and serious life-threatening infections, and contributes to increased mortality in immunocompromised individuals.P.aeruginosainfection triggers host immune response and often provokes potent inflammatory mediators, which do not necessarily eradicate the causative pathogen. On the other hand, it causes severe airway damage and eventually decreased lung function. Such unfavorable outcomes of inflammatory injury have necessitated the development of novel effective agents that can combat withP.aeruginosa-mediated inflammation. Herein, we investigated the potential of quercetin in regulatingP.aeruginosa-induced inflammation, with particular emphasized on the interleukin-1 beta (IL-1 beta). Our results showed that quercetin exerted the potent inhibitory activity against the production of IL-1 beta in macrophages infected by liveP.aeruginosaPAO1, without exhibiting cytotoxicity. According to our settings, such the potent inhibitory activity of quercetin was clearly demonstrated through its ability to efficiently inhibit IL-1 beta duringP.aeruginosainfection, pre- or even post-infection. In addition, quercetin strongly suppressed MAPK signaling pathway by inhibiting phosphorylation of the p38 MAPK and JNK2, and molecular docking study supported well with this observation. Moreover, quercetin reduced the NLRP3 expression and inhibited theP.aeruginosa-mediated cleavage of caspase-1 as well as mature IL-1 beta. These results thus indicated that quercetin inhibition ofP.aeruginosa-induced IL-1 beta production is mediated by suppressing the initial priming step and by inhibiting the NLRP3 inflammasome activation. Taken together, our findings demonstrated the promising regulatory activity of quercetin against IL-1 beta production inP.aeruginosa-infected macrophages, and indicated that quercetin has the potential to be effective as a novel therapeutic agent for treatment ofP.aeruginosa-induced inflammation.