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

Zha, Qing Bing; Wei, Hong; Li, Chen Guang; Liang, Yi Dan; Xu, Lihui; Bai, Wen; Pan, Hao; He, Xian; Ouyang, Dong-Yun

doi:10.3389/fimmu.2016.00597

Cited by 76 publications

(54 citation statements)

References 61 publications

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“…4a-d). Extracellular ATP activates the NLRP3-ASC-inflammasome axis leading to secretion of mature IL-1β 36,37 . Ad-infection is associated with sustained autophagy (Fig.…”

Section: Discussionmentioning

confidence: 99%

Characterization of virus-mediated immunogenic cancer cell death and the consequences for oncolytic virus-based immunotherapy of cancer

et al. 2020

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Oncolytic viruses have the potential to induce immunogenic cell death (ICD) that may provoke potent and longlasting anti-cancer immunity. Here we aimed to characterize the ICD-inducing ability of wild-type Adenovirus (Ad), Semliki Forest virus (SFV) and Vaccinia virus (VV). We did so by investigating the cell death and immune-activating properties of virus-killed tumor cells. Ad-infection of tumor cells primarily activates autophagy, but also activate events of necroptotic and pyroptotic cell death. SFV infection on the other hand primarily activates immunogenic apoptosis while VV activates necroptosis. All viruses mediated lysis of tumor cells leading to the release of danger-associated molecular patterns, triggering of phagocytosis and maturation of dendritic cells (DCs). However, only SFV-infected tumor cells triggered significant T helper type 1 (Th1)-cytokine release by DCs and induced antigen-specific T-cell activation. Our results elucidate cell death processes activated upon Ad, SFV, and VV infection and their potential to induce T cell-mediated anti-tumor immune responses. This knowledge provides important insight for the choice and design of therapeutically successful virus-based immunotherapies.

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“…4a-d). Extracellular ATP activates the NLRP3-ASC-inflammasome axis leading to secretion of mature IL-1β 36,37 . Ad-infection is associated with sustained autophagy (Fig.…”

Section: Discussionmentioning

confidence: 99%

Characterization of virus-mediated immunogenic cancer cell death and the consequences for oncolytic virus-based immunotherapy of cancer

et al. 2020

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“…To the best of our knowledge, this is the first study to report PD-induced NLRP3 inflammasome inactivation as a molecular mechanism of mitophagy in SI-AKI. Increasing studies have reported that inflammasome formation-induced activation of pyroptosis plays an important role in inflammatory diseases, including SI-AKI [39][40][41]. In the future, the effects of PD and sirtuins on pyroptosis should be explored further to identify more treatment targets for SI-AKI.…”

Section: Discussionmentioning

confidence: 99%

Role of Parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury

Gao

Dai

et al. 2020

J Transl Med

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Background: We have reported that polydatin (PD) alleviates mitochondrial dysfunction in rat models of sepsisinduced acute kidney injury (SI-AKI), but the mechanism is not well understood. Here, we investigated the role of Parkin-mediated mitophagy in the protective effects of PD in SI-AKI in mice. Methods: Sepsis was induced in the mice by caecal ligation and puncture. Mitophagy was determined by mitochondrial mass. NLRP3 inflammasome activation was determined by NLRP3, ASC and caspase-1. Mitophagy was blocked by treatment with mitochondrial division inhibitor-1 and Parkin knockout. Key results: PD treatment increased the sepsis-induced loss of mitochondrial mass, indicating the upregulation of mitophagy. Furthermore, PD treatment mediated Parkin translocation from the cytoplasm to the mitochondria. This suggests that Parkin-mediated mitophagy is an underlying mechanism. This was confirmed by the suppression of PD-induced mitophagy in Parkin−/− mice and in mice that were treated with a mitophagy inhibitor. PD-induced Parkin translocation and mitophagy were blocked by inhibiting SIRT1; thus, activation of SIRT1 might be an important molecular mechanism that is triggered by PD. Additionally, PD treatment protected against sepsis-induced kidney injury. These effects were blocked by inhibition of Parkin-dependent mitophagy. Furthermore, PD also protected against mitochondrial dysfunction and mitochondria-dependent apoptosis, and the effect was blocked when Parkindependent mitophagy was inhibited. Finally, PD suppressed NLRP3 inflammasome activation that was also dependent on Parkin-mediated mitophagy. Conclusions: These findings indicate that Parkin-mediated mitophagy is important for the protective effect of PD in SI-AKI, and the underlying mechanisms include the inhibition of mitochondrial dysfunction and NLRP3 inflammasome activation.

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“…In support of this, it has been deduced that the extent of pyroptosis determines the magnitude of inflammation, and the controlled pyroptosis plays a crucial role in limiting the extent of inflammation and maintains a hemostasis state, as was observed in the early and chronic stage of apical periodontitis. 15 Further, a study by Zha et al (2016) also reported that inflammasome activation was enhanced in metformin-treated mice upon bacterial infection. 19 Moreover, our observations revealed a strong and positive correlation of AMPK⍺(T172) with NLRP3 levels in the metformin group.…”

Section: Discussionmentioning

confidence: 97%

“…15 Further, a study by Zha et al (2016) also reported that inflammasome activation was enhanced in metformin-treated mice upon bacterial infection. 19 Moreover, our observations revealed a strong and positive correlation of AMPK⍺(T172) with NLRP3 levels in the metformin group. Based on these findings, enhanced NLRP3 expression and increased mitophagy could be attributed to the metformin-induced increased AMPK phosphorylation, as AMPK activation indirectly or directly regulates the phosphorylation of NLRP3 and mitophagic proteins.…”

Section: Discussionmentioning

confidence: 97%

“…Recently, it has also been discovered that AMPK positively regulates autophagy, and metformin has been shown to activate autophagy via AMPK . In addition, prior evidence also demonstrated that AMPK is involved in the inflammasome activation and pyroptosis in LPS‐primed macrophages . However, the molecular mechanism of action of metformin in the regulation of mitophagy and NLRP3 still remains to be largely explored.…”

Section: Introductionmentioning

confidence: 99%

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Metformin upregulates mitophagy in patients with T2DM: A randomized placebo‐controlled study

Bhansali

Dutta

et al. 2020

J Cellular Molecular Medi

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Impaired mitochondrial autophagy (mitophagy) and NLRP3 inflammasome activation have been incriminated in the pathogenesis of T2DM. Metformin besides being an insulin sensitizer also induces autophagy; however, its effect on mitophagy and NLRP3 activation in patients with T2DM still remains elusive. Forty‐five drug‐naïve T2DM patients with HbA1C 7%‐9% (53‐75 mmol/mol) were randomly assigned to receive either metformin, voglibose, or placebo for 3 months, and were also recommended for lifestyle intervention programme (n = 15 each). Mitochondrial oxidative stress (MOS) parameters, qPCR and immunoblotting of mitophagy‐related markers (PINK1, PARKIN, MFN2, NIX, LC3‐II, LAMP2), p‐AMPKα (T172), and NLRP3 proteins, as well as transmission electron microscopy (TEM) for assessing mitochondrial morphology were performed in the mononuclear cells of study patients. Both metformin and voglibose showed a similar efficacy towards the reduction in HbA1c and MOS indices. However, multivariate ANCOVA divulged that mRNA and protein expression of mitophagy markers, NLRP3 and p‐AMPKα (T172), were significantly increased only with metformin therapy. Moreover, PINK1 expression displayed a significant positive association with HOMA‐β indices, and TEM studies further confirmed reduced distortions in mitochondrial morphology in the metformin group only. Our observations underscore that metformin upregulates mitophagy and subsequently ameliorates the altered mitochondrial morphology and function, independent of its glucose‐lowering effect. Further, restoration of normal mitochondrial phenotype may improve cellular function, including β‐cells, which may prevent further worsening of hyperglycaemia in patients with T2DM.

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

Cited by 76 publications

References 61 publications

Characterization of virus-mediated immunogenic cancer cell death and the consequences for oncolytic virus-based immunotherapy of cancer

Characterization of virus-mediated immunogenic cancer cell death and the consequences for oncolytic virus-based immunotherapy of cancer

Role of Parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury

Metformin upregulates mitophagy in patients with T2DM: A randomized placebo‐controlled study

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