Gossypol induces pyroptosis in mouse macrophages via a non-canonical inflammasome pathway

Lin, Qiu-Ru; Li, Chenguang; Zha, Qing-Bing; Xu, Lihui; Pan, Hao; Zhao, Guiqiu; Ouyang, Dong-Yun; He, Xian-Hui

doi:10.1016/j.taap.2015.12.027

Cited by 25 publications

(18 citation statements)

References 32 publications

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“…Cell pyroptosis was measured as described previously (24, 25). Briefly, cells were seeded in 24-well plates and cultured for 24 h. The cells were then primed with 500 ng/ml LPS for 4 h followed by treatment with indicated concentrations of metformin in Opti-MEM for 1 h. Next, indicated concentrations of ATP were added to the culture medium for indicated time periods.…”

Section: Methodsmentioning

confidence: 99%

ATP-Induced Inflammasome Activation and Pyroptosis Is Regulated by AMP-Activated Protein Kinase in Macrophages

Zha

Wei

et al. 2016

Front. Immunol.

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Adenosine triphosphate (ATP) is released by bacteria and host cells during bacterial infection as well as sterile tissue injury, acting as an inducer of inflammasome activation. Previous studies have shown that ATP treatment leads to AMP-activated protein kinase (AMPK) activation. However, it is unclear whether AMPK signaling has been involved in the regulation of ATP-induced inflammasome activation and subsequent pyroptosis. In this study, we aimed to investigate this issue in lipopolysaccharide-activated murine macrophages. Our results showed that AMPK signaling was activated in murine macrophages upon ATP treatment, which was accompanied by inflammasome activation and pyroptosis as evidenced by rapid cell membrane rupture as well as mature interleukin (IL)-1β and active caspase-1p10 release. The ATP-induced inflammasome activation and pyroptosis were markedly suppressed by an AMPK inhibitor compound C or small-interfering RNA-mediated knockdown of AMPKα, but could be greatly enhanced by metformin (a well-known AMPK agonist). Importantly, metformin administration increased the mortality of mice with bacterial sepsis, which was likely because metformin treatment enhanced the systemic inflammasome activation as indicated by elevated serum and hepatic IL-1β levels. Collectively, these data indicated that the AMPK signaling positively regulated ATP-induced inflammasome activation and pyroptosis in macrophages, highlighting the possibility of AMPK-targeting therapies for inflammatory diseases involving inflammasome activation.

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Section: Methodsmentioning

confidence: 99%

ATP-Induced Inflammasome Activation and Pyroptosis Is Regulated by AMP-Activated Protein Kinase in Macrophages

Zha

Wei

et al. 2016

Front. Immunol.

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“…Proteins in culture supernatants (equal volume for each sample) were precipitated overnight with 7.2% trichloroacetic acid plus 0.15% sodium deoxycholate as previously described ( Lin et al, 2016 ). The precipitates are lysed in equal volume of 1x sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) loading buffer.…”

Section: Methodsmentioning

confidence: 99%

Piperine Suppresses Pyroptosis and Interleukin-1β Release upon ATP Triggering and Bacterial Infection

Liang

Bai

et al. 2016

Front. Pharmacol.

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Piperine is a phytochemical present in black pepper (Piper nigrum Linn) and other related herbs, possessing a wide array of pharmacological activities including anti-inflammatory effects. Previously, we demonstrated that piperine has therapeutic effects on bacterial sepsis in mice, but the underlying mechanism has not been fully elucidated. In this study, we aimed to investigate the influences of piperine on pyroptosis in murine macrophages. The results showed that piperine dose-dependently inhibited ATP-induced pyroptosis, thereby suppressing interleukin-1β (IL-1β) or high mobility group box-1 protein (HMGB1) release in LPS-primed bone marrow-derived macrophages and J774A.1 cells. Accompanying this, ATP-induced AMP-activated protein kinase (AMPK) activation was greatly suppressed by piperine, whereas AMPK agonist metformin counteracted piperine’s inhibitory effects on pyroptosis. Moreover, piperine administration greatly reduced both peritoneal and serum IL-1β levels in the mouse model intraperitoneally infected with Escherichia coli, suggestive of suppressing systemic inflammation and pyroptosis. Our data indicated that piperine could protect macrophages from pyroptosis and reduced IL-1β and HMGB1 release by suppressing ATP-induced AMPK activation, suggesting that piperine may become a potential therapeutic agent against bacterial sepsis.

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“…The separation of TG-elicited peritoneal macrophages (TGPMs) was performed as described previously [42]. Briefly, mice were administered intraperitoneally with 1 ml of 3% TG medium and sacrificed 4 d later.…”

Section: Methodsmentioning

confidence: 99%

“…Cell death was measured by PI incorporation as described previously [25, 42]. Cells were seeded in 24-well plates and primed with 500 ng/ml LPS for 4 h. Subsequently, the cells were treated with various concentrations of berberine for 1 h followed by appropriate concentration of ATP for indicated time periods in Opti-MEM.…”

Section: Methodsmentioning

confidence: 99%

Berberine augments ATP-induced inflammasome activation in macrophages by enhancing AMPK signaling

Liang

Jing

et al. 2016

Oncotarget

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The isoquinoline alkaloid berberine possesses many pharmacological activities including antibacterial infection. Although the direct bactericidal effect of berberine has been documented, its influence on the antibacterial functions of macrophages is largely unknown. As inflammasome activation in macrophages is important for the defense against bacterial infection, we aimed to investigate the influence of berberine on inflammasome activation in murine macrophages. Our results showed that berberine significantly increased ATP-induced inflammasome activation as reflected by enhanced pyroptosis as well as increased release of caspase-1p10 and mature interleukin-1β (IL-1β) in macrophages. Such effects of berberine could be suppressed by AMP-activated protein kinase (AMPK) inhibitor compound C or by knockdown of AMPKα expression, indicating the involvement of AMPK signaling in this process. In line with increased IL-1β release, the ability of macrophages to kill engulfed bacteria was also intensified by berberine. This was corroborated by the in vivo finding that the peritoneal live bacterial load was decreased by berberine treatment. Moreover, berberine administration significantly improved survival of bacterial infected mice, concomitant with increased IL-1β levels and elevated neutrophil recruitment in the peritoneal cavity. Collectively, these data suggested that berberine could enhance bacterial killing by augmenting inflammasome activation in macrophages through AMPK signaling.

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Gossypol induces pyroptosis in mouse macrophages via a non-canonical inflammasome pathway

Cited by 25 publications

References 32 publications

ATP-Induced Inflammasome Activation and Pyroptosis Is Regulated by AMP-Activated Protein Kinase in Macrophages

ATP-Induced Inflammasome Activation and Pyroptosis Is Regulated by AMP-Activated Protein Kinase in Macrophages

Piperine Suppresses Pyroptosis and Interleukin-1β Release upon ATP Triggering and Bacterial Infection

Berberine augments ATP-induced inflammasome activation in macrophages by enhancing AMPK signaling

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