Abstract
Pseudomonas aeruginosa remains a leading cause of nosocomial and serious life-threatening infections, and contributes to increased mortality in immunocompromised individuals. P. aeruginosa infection 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 with P. aeruginosa-mediated inflammation. Herein, we investigated the potential of quercetin in regulating P. aeruginosa-induced inflammation, with particular emphasized on the interleukin-1β (IL-1β). Our results showed that quercetin exerted the potent inhibitory activity against the production of IL-1β in macrophages infected by live P. aeruginosa PAO1, without exhibiting cytotoxicity. According to our settings, such the potent inhibitory activity of quercetin was clearly demonstrated through its ability to efficiently inhibit IL-1β during P. aeruginosa infection, 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 the P. aeruginosa-mediated cleavage of caspase-1 as well as mature IL-1β. These results thus indicated that quercetin inhibition of P. aeruginosa-induced IL-1β 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-1β production in P. aeruginosa-infected macrophages, and indicated that quercetin has the potential to be effective as a novel therapeutic agent for treatment of P. aeruginosa-induced inflammation.
Highlights
Pseudomonas aeruginosa is a Gram-negative bacterium and an opportunistic pathogen capable of infecting humans with compromised host defense mechanisms [1] and causing serious infections and even death [2,3,4]
There was no differences in bacterial growth between vehicle and untreated control. These results suggested that quercetin at the concentrations studied had no impact on growth of P. aeruginosa PAO1, and 20–100 μM of such a compound was used in the following experiments
We further investigated if this pathway may be used by quercetin to exert its inhibitory effect on the release of IL-1β produced by P. aeruginosa-infected THP-1 macrophages
Summary
Pseudomonas aeruginosa is a Gram-negative bacterium and an opportunistic pathogen capable of infecting humans with compromised host defense mechanisms [1] and causing serious infections and even death [2,3,4]. When in excess or inappropriate production, these inflammatory mediators are harmful to the host, causing severe airway damage and decreased lung function [7]. Antibiotic treatment of such chronic P. aeruginosa infection may temporarily suppress the symptoms but they do not necessarily eradicate the causative pathogen. Chronic lung infections with P. aeruginosa and its associated inflammation is considered to be responsible for significant morbidity and mortality in CF patients [8, 9]
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