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Activation of NLRP3 inflammasome up-regulates TREM-1 expression in murine macrophages via HMGB1 and IL-18.

ABSTRACT: NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome and triggering receptor expressed on myeloid cells-1 (TREM-1) are considered critical orchestrators of the inflammatory response in acute lung injury (ALI). However, few assumptions are based on the relationship between them. Here, we investigated the effect of NLRP3 inflammasome activation on the TREM-1 expression in lipopolysaccharide (LPS)-induced ALI and macrophages. We found that inhibition of the NLRP3 inflammasome reduced the TREM-1 expression and pathological lung injury in mice with ALI. Then, primary murine macrophages were used to dissect the underlying mechanistic events of the activation NLRP3 inflammasome involved in the TREM-1 expression. Our results demonstrated that the conditioned medium (CM) from NLRP3 inflammasome-activated-macrophages up-regulated the TREM-1 expression in macrophages, while this effect was reversed by an NLRP3 inflammasome inhibitor MCC950. Furthermore, neutralizing antibodies anti-IL-18 and anti-HMGB1 reduced the TREM-1 expression induced by NLRP3 inflammasome activation. Mechanistically, we found that CM from NLRP3 inflammasome-activated-macrophages increased the level of inhibitor ?B kinase protein phosphorylation (p-I?B?) and reactive oxygen species (ROS) content, and promoted I?B? protein degradation in macrophages. While the inhibition of nuclear factor kappa-B (NF-?B) and scavenging ROS eliminated the up-regulation of TREM-1 induced by the NLRP3 inflammasome activation in macrophages. In summary, our study confers NLRP3 inflammasome as a new trigger of TREM-1 signing, which allows additional insight into the pathological of the inflammatory response in ALI.

SUBMITTER: Zhong WJ

PROVIDER: S-EPMC7545267 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Activation of NLRP3 inflammasome up-regulates TREM-1 expression in murine macrophages via HMGB1 and IL-18.

Zhong Wen-Jing WJ Duan Jia-Xi JX Liu Tian T Yang Hui-Hui HH Guan Xin-Xin XX Zhang Chen-Yu CY Yang Jin-Tong JT Xiong Jian-Bing JB Zhou Yong Y Guan Cha-Xiang CX Li Qing Q

International immunopharmacology 20201009 Pt A

NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome and triggering receptor expressed on myeloid cells-1 (TREM-1) are considered critical orchestrators of the inflammatory response in acute lung injury (ALI). However, few assumptions are based on the relationship between them. Here, we investigated the effect of NLRP3 inflammasome activation on the TREM-1 expression in lipopolysaccharide (LPS)-induced ALI and macrophages. We found that inhibition of the NLRP3 inflammasome reduced the T ...[more]

PMID: 33045564

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Project description: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-1? (IL-1?). Our results showed that quercetin exerted the potent inhibitory activity against the production of IL-1? 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-1? 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-1?. These results thus indicated that quercetin inhibition of P. aeruginosa-induced IL-1? 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? 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.

Dataset Information

Activation of NLRP3 inflammasome up-regulates TREM-1 expression in murine macrophages via HMGB1 and IL-18.

Publications

Activation of NLRP3 inflammasome up-regulates TREM-1 expression in murine macrophages via HMGB1 and IL-18.

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