ATP induces caspase-3/gasdermin E-mediated pyroptosis in NLRP3 pathway-blocked murine macrophages

Zeng, Chengli; Li, Chenguang; Shu, Jun-Xiang; Xu, Lihui; Ouyang, Dong-Yun; Mai, Feng-Yi; Zeng, Qian; Zhang, Chengcheng; Li, Rui-Man; He, Xian-Hui

doi:10.1007/s10495-019-01551-x

Cited by 70 publications

(53 citation statements)

References 56 publications

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“…Our results demonstrated that GSDME also functions as a critical target of chemotherapy drug-induced AKI. Similar to that of other reports 40,44,45 , our in vitro results indicated that GSDME knockout alleviated renal tubular epithelial cell pyroptosis. In vivo, the Gsdme-derived inhibitor, Ac-DMLD-CMK, alleviated deterioration of kidney function, attenuated renal tubular epithelial cell injury, reduced inflammatory cytokine secretion, and inhibited caspase 3-GSDME signaling induced by cisplatin.…”

Section: Discussionsupporting

confidence: 92%

“…Pyroptosis can be induced by caspase 4 and 5 (in humans) or caspase 11 (in mice) activation via GSDMD cleavage, leading to cell bubbling and the release of IL-1β 21,[36][37][38] . Recently discovered caspase 3/GSDME signaling was also reported to be one of the signaling mechanisms for cell pyroptosis 14,28,[39][40][41] . Moreover, GSDMEpositive cancer cells reportedly undergo pyroptosis, while GSDME-negative cancer cells undergo apoptosis upon stimulation with chemotherapy drugs 14,27 .…”

Section: Discussionmentioning

confidence: 99%

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Caspase 3/GSDME-dependent pyroptosis contributes to chemotherapy drug-induced nephrotoxicity

et al. 2021

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Chemotherapy drug-induced nephrotoxicity limits clinical applications for treating cancers. Pyroptosis, a newly discovered programmed cell death, was recently reported to be associated with kidney diseases. However, the role of pyroptosis in chemotherapeutic drug-induced nephrotoxicity has not been fully clarified. Herein, we demonstrate that the chemotherapeutic drug cisplatin or doxorubicin, induces the cleavage of gasdermin E (GSDME) in cultured human renal tubular epithelial cells, in a time- and concentration-dependent manner. Morphologically, cisplatin- or doxorubicin-treated renal tubular epithelial cells exhibit large bubbles emerging from the cell membrane. Furthermore, activation of caspase 3, not caspase 9, is associated with GSDME cleavage in cisplatin- or doxorubicin-treated renal tubular epithelial cells. Meanwhile, silencing GSDME alleviates cisplatin- or doxorubicin-induced HK-2 cell pyroptosis by increasing cell viability and decreasing LDH release. In addition, treatment with Ac-DMLD-CMK, a polypeptide targeting mouse caspase 3-Gsdme signaling, inhibits caspase 3 and Gsdme activation, alleviates the deterioration of kidney function, attenuates renal tubular epithelial cell injury, and reduces inflammatory cytokine secretion in vivo. Specifically, GSDME cleavage depends on ERK and JNK signaling. NAC, a reactive oxygen species (ROS) inhibitor, reduces GSDME cleavage through JNK signaling in human renal tubular epithelial cells. Thus, we speculate that renal tubular epithelial cell pyroptosis induced by chemotherapy drugs is mediated by ROS-JNK-caspase 3-GSDME signaling, implying that therapies targeting GSDME may prove efficacious in overcoming chemotherapeutic drug-induced nephrotoxicity.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Caspase 3/GSDME-dependent pyroptosis contributes to chemotherapy drug-induced nephrotoxicity

et al. 2021

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“…The inflammasome is a type of multimeric protein complex. Studies have found that a variety of factors (such as ATP, Zeng et al, 2019; ROS, Jiang et al, 2018; glucose, Gu et al, 2019) can activate NLRP3 to induce pyroptosis. In this study, MEHP exposure could augment Caspase‐1 and NLRP3 expression in HEMECs according to western blot results.…”

Section: Discussionmentioning

confidence: 99%

Exposure to mono (2‐ethylhexyl) phthalate facilitates apoptosis and pyroptosis of human endometrial microvascular endothelial cells through NLRP3 inflammasome

2020

J of Applied Toxicology

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Mono (2‐ethylhexyl) phthalate (MEHP) is a major metabolite of di (2‐ethylhexyl) phthalate (DEHP). This study aimed to observe the toxic effect of MEHP on human endometrial microvascular endothelial cells (HEMECs) and its potential molecular mechanism. HEMECs were exposed to different concentrations of MEHP (0, 50, 100, and 200 nM). Cell viability and apoptosis were assessed by cell counting kit‐8 (CCK‐8) and flow cytometry assays. Western blot was performed to examine the expression of apoptosis‐related proteins (Bcl‐2, Bax, and Caspase‐3). Moreover, the expression of pyroptosis‐related Caspase‐1 was detected by western blot and immunofluorescence assays. Lactate dehydrogenase (LDH) release levels were evaluated in HEMECs treated with MEHP and/or Caspase‐1 inhibitor Ac‐YVAD‐CHO. After exposure to MEHP, NLRP3 expression was examined by reverse transcription quantitative polymerase chain reaction (RT‐qPCR) and western blot. LDH release and apoptosis levels were tested in HEMECs induced by MEHP and/or siNLRP3. MEHP significantly induced cell viability and inhibited apoptosis for HEMECs, with a concentration‐dependent manner. Furthermore, Bcl‐2/Bax ratio was distinctly reduced and Caspase‐3 expression was increased in HEMECs after exposure to MEHP. Western blot and immunofluorescence results confirmed that MEHP markedly augmented Caspase‐1 expression in HEMECs. Furthermore, LDH release levels were fortified in HEMECs treated with MEHP, which were improved following cotreatment with Ac‐YVAD‐CHO. At the mRNA and protein levels, NLRP3 expression was prominently increased in HEMECs exposed to MEHP. NLRP3 knockdown markedly ameliorated the increase in LDH release and apoptosis induced by MEHP exposure in HEMECs. Our findings suggested that exposure to MEHP facilitates apoptosis and pyroptosis of HEMECs through NLRP3 inflammasome.

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“…At the end of a short LPS triggered pathway (LPS sensing activates caspase 4 and caspase-5 to cleave GSDMD, causing membrane permeabilization and subsequent NLRP3 inflammasome assembly. The NLRP3 inflammasome stimulates caspase 1 to unleash a second wave of GSDMD activity and the sole wave of pro-IL-1 processing [ 141 ]. Disulfiram (Antabuse) has been identified as a GSDMD inhibitor representing an attractive therapeutic approach [ 142 ], as well as, the NLRP3 inhibitor, OLT1177 (Dapansutrile) ( Table 2 ) [ 50 , 143 ].…”

Section: Gasdermin D and Gasdermin Ementioning

confidence: 99%

Non-Small-Cell Lung Cancer Signaling Pathways, Metabolism, and PD-1/PD-L1 Antibodies

Santarpía

Aguilar

Chaib

et al. 2020

Cancers

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Treatment of advanced (metastatic) non-small-cell lung cancer (NSCLC) is currently mainly based on immunotherapy with antibodies against PD-1 or PD-L1, alone, or in combination with chemotherapy. In locally advanced NSCLC and in early resected stages, immunotherapy is also employed. Tumor PD-L1 expression by immunohistochemistry is considered the standard practice. Response rate is low, with median progression free survival very short in the vast majority of studies reported. Herein, numerous biological facets of NSCLC are described involving driver genetic lesions, mutations ad fusions, PD-L1 glycosylation, ferroptosis and metabolic rewiring in NSCLC and lung adenocarcinoma (LUAD). Novel concepts, such as immune-transmitters and the effect of neurotransmitters in immune evasion and tumor growth, the nascent relevance of necroptosis and pyroptosis, possible new biomarkers, such as gasdermin D and gasdermin E, the conundrum of K-Ras mutations in LUADs, with the growing recognition of liver kinase B1 (LKB1) and metabolic pathways, including others, are also commented. The review serves to charter diverse treatment solutions, depending on the main altered signaling pathways, in order to have effectual immunotherapy. Tumor PDCD1 gene (encoding PD-1) has been recently described, in equilibrium with tumor PD-L1 (encoded by PDCD1LG1). Such description explains tumor hyper-progression, which has been reported in several studies, and poises the fundamental criterion that IHC PD-L1 expression as a biomarker should be revisited.

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ATP induces caspase-3/gasdermin E-mediated pyroptosis in NLRP3 pathway-blocked murine macrophages

Cited by 70 publications

References 56 publications

Caspase 3/GSDME-dependent pyroptosis contributes to chemotherapy drug-induced nephrotoxicity

Caspase 3/GSDME-dependent pyroptosis contributes to chemotherapy drug-induced nephrotoxicity

Exposure to mono (2‐ethylhexyl) phthalate facilitates apoptosis and pyroptosis of human endometrial microvascular endothelial cells through NLRP3 inflammasome

Non-Small-Cell Lung Cancer Signaling Pathways, Metabolism, and PD-1/PD-L1 Antibodies

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