Anti-PD-1 exacerbates bleomycin-induced lung injury in mice via Caspase-3/GSDME-mediated pyroptosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE280068 | GEO | 2024/12/23
REPOSITORIES: GEO
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Project description:Anti-PD-1 exacerbates bleomycin-induced lung injury in mice via Caspase-3/GSDME-mediated pyroptosis
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Project description:It is widely acknowledged that gasdermin family proteins, which are known as the executors of pyroptosis, undergo protease-mediated cleavage prior to inducing pyroptosis. Here, we unexpectedly discovered a non-canonical form of pyroptosis mediated by full-length GSDME (FL-GSDME) without any proteolytic cleavage. Upon intense ultraviolet (UV) irradiation-triggered DNA damage, hyperactivation of nuclear PARP1 led to extensive formation of poly(ADP-ribose) (PAR) polymers and then release to the cytoplasm.These PAR polymers activate PARP5 to catalyze GSDME PARylation, resulted in a conformational change in GSDME that relieved autoinhibition imposed by its C terminus on the N terminus. On the other hand, intense UV irradiation boosted mitochondrial fission-dependent generation of mitochondrial reactive oxygen species (mito-ROS), further promoting cytochrome c-catalyzed peroxidation of cardiolipin. This lipid-ROS signal was then sensed by PARylated-GSDME and then induced oxidative oligomerization of GSDME, which facilitated FL-GSDME plasma membrane targeting for perforation, eventually inducing pyroptosis. Reagents that concurrently stimulate PARPs activity and lipid-ROS also induced sequential modifications i.e., PARylation and oxidation of FL-GSDME and synergistically promoted pyroptotic cell death. Overall, our findings elucidate a novel mechanism underlying cleavage-independent function of GSDME in executing cell demise, further enriching the paradigms and cognition of FL-GSDME-mediated non-canonical pyroptosis.
2024-06-17 | PXD051840 | Pride
Project description:Summary Sodium 4-phenylbutyrate (Na-PBA), a histone deacetylase inhibitor, shows potential in mitigating acute lung injury (ALI) by addressing endothelial cell injury. In a lipopolysaccharide (LPS)-induced ALI mouse model, Na-PBA pretreatment reduced lung damage, pulmonary edema, and inflammatory markers, while decreasing oxidative stress and endothelial pyroptosis via the cytochrome c-caspase9-caspase3-GSDME pathway. In vitro studies with human umbilical vein endothelial cells (HUVECs) confirmed that Na-PBA enhanced PARK7 expression, which is crucial for its protective effects against oxidative damage and pyroptosis. The mechanism involves PARK7 stabilizing mitochondria and inhibiting cytochrome c leakage, leading to reduced caspase activation. Na-PBA's effects are mediated through upregulation of PARK7, potentially within a positive feedback loop involving NRF2. These findings identify a novel therapeutic strategy to alleviate endothelial injury in lung diseases.
2025-01-07 | GSE285730 | GEO
Project description:Acute kidney injury(AKI) is associated with an increased risk of chronic kidney disease(CKD). There is still a lack of effective prevention for AKI-CKD transition. In the present study, we simultaneously explored the contribution of GSDMD and GSDME in folic acid (FA)-induced nephropathy, a model mimicking the essential components of the AKI-CKD transition. We found that blockage of both GSDMD and GSDME-mediated pyroptosis could have accumulative protection against FA-induced AKI-CKD transition. GSDME-mediated pyroptosis played a crucial role in tubular cell damage. GSDMD could exert important functions in infiltration of inflammatory cells and NETs formation. Pyroptotic tubular cells triggered NETs generation and macrophage polarization. NETs promoted macrophage-to-myofibroblast transition. Our results illustrated the orchestration of GSDMD and GSDME in AKI-CKD transition, providing new insights into the molecular mechanism for the clinical dilemma.
2024-10-31 | GSE245446 | GEO
Project description:Cannabidiol (CBD), a phytochemical derived from Cannabis sativa L., has been demonstrated to exhibit promising anti-tumor properties in multiple cancer types. However, the effects of CBD on Hepatocellular carcinoma cells (HCC) remains unknown. We have shown that CBD effectively suppresses HCC cell growth in vivo and in vitro, and induced HCC cell pyroptosis in a caspase-3/GSDME-dependent manner. We further demonstrated that accumulation of Integrative Stress Response (ISR) and mitochondrial stress may contribute to the initiation of pyroptotic signaling by CBD. Simultaneously, CBD can repress aerobic glycolysis through modulation of the ATF4-IGFBP1-Akt axis, due to the depletion of ATP and crucial intermediate metabolites. Collectively, these observations indicate that CBD could be considered as a potential compound for HCC therapy.
2021-07-14 | GSE179661 | GEO
Project description:A novel mechanism of Cannabidiol in suppressing hepatocellular carcinoma by inducing GSDME dependent pyroptosis
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Project description:Sarcopenia has become a leading cause of disability and mortality in the elderly. It has been reported that programmed cell death (PCD) is associated with the development of sarcopenia that is characterized by reduction of muscle fiber size and number. TNF-α is also validated to play a prominent role in sarcopenia through its complex signaling pathways including cell death signaling. However, it is still unclear whether TNF-α contributes to sarcopenia by mediating pyroptosis, one type of PCD. Here, we first established naturally aged mice with sarcopenia model and confirmed an inflammatory state represented by TNF-α in aged mice. Evidence of GSDME-mediated pyroptosis and activation of apoptotic caspase-8/-3 were also found in skeletal muscle cells of aged mice with sarcopenia. We demonstrated that TNF-α triggered GSDME-mediated pyroptosis in myotubes through activating caspase-8 and caspase-3 by using caspase-8 and caspase-3 inhibitors. Comparing the activation of caspase-8 and GSDME expression between TNF Complex IIa and TNF Complex IIb, TNF-α was found to be more inclined to assemble TNF Complex IIb in activating caspase-8 and triggering pyroptosis. Moreover, pyroptotic myotubes were validated to result in decreased expression of MHC1 and finally loss of myotubes by knockdown of GSDME. Our work reveals a novel mechanism that TNF-ɑ/caspase-8/caspase-3/GSDME signaling-mediated pyroptosis contributes to the development of sarcopenia. Caspase-3/GSDME signaling-mediated pyroptosis may be a promising therapeutic target for sarcopenia.
| S-EPMC9950087 | biostudies-literature
Project description:Acidic tumor microenvironment (TME)-evoked MRC nanoparticles (MRC NPs) co-delivering immune agonist RGX-104 and photosensitizer chlorine e6 (Ce6) are reported for pyroptosis-mediated immunotherapy. RGX-104 remodels TME by transcriptional activation of ApoE to regress myeloid-derived suppressor cells’ (MDSCs) activity, which neatly creates foreshadowing for intensifying pyroptosis. Considering Ce6-triggered photodynamic therapy (PDT) can strengthen oxidative stress and organelles destruction to increase immunogenicity, immunomodulatory-photodynamic MRC nanodrugs will implement an aforementioned two-pronged strategy to enhance gasdermin E (GSDME)-dependent pyroptosis. RNA-seq analysis of MRC at the cellular level is introduced to first elucidate the intimate relationship between RGX-104 acting on LXR/ApoE axis and pyroptosis, where RGX-104 provides the prerequisite for pyroptosis participating in antitumor therapy. Briefly, MRC with favorable biocompatibility tackles the obstacle of hydrophobic drugs delivery, and becomes a powerful pyroptosis inducer to reinforce immune efficacy. MRC-elicited pyroptosis in combination with anti-PD-1 blockade therapy boosts immune response in solid tumors, successfully arresting invasive metastasis and extending survival based on remarkable antitumor immunity. MRC may initiate a new window for immuno-photo pyroptosis stimulators augmenting pyroptosis-based immunotherapy. Owing to the transcriptome sequencing on 4T1 cells exposed to various treatment, pyroptosis mechanism of MRC was thoroughly analyzed via comparing the expression discrepancy among PBS, MRC, and MRC+L groups.
2023-08-13 | GSE240328 | GEO
Project description:Pyroptosis, a newly discovered mode of programmed cell death (PCD), is important in the regulation of cancer development. High mobility group box 1 (HMGB1) is a non-histone nuclear protein that is closely related to tumor development and chemotherapy resistance. However, whether endogenous HMGB1 regulates pyroptosis in neuroblastoma remains unknown. Here, we showed that HMGB1 showed ubiquitous higher expression in SH-SY5Y cells and clinical tumors, and was positively correlated with the risk factors of patients with neuroblastoma. Knockdown of GSDME or pharmacological inhibition of caspase-3 blocked pyroptosis and cytosolic translocation of HMGB1. Moreover, knockdown of HMGB1 inhibited cisplatin (DDP) or etoposide (VP16)-induced pyroptosis by decreasing GSDME-NT and cleaved caspase-3 expression, resulting in cell blebbing and LDH release. Knockdown of HMGB1 expression increased the sensitivity of SH-SY5Y cells to chemotherapy and switched pyroptosis to apoptosis. Furthermore, the ROS/ERK1/2/caspase-3/GSDME pathway was found to be functionally connected with DDP or VP16-induced pyroptosis. Hydrogen peroxide (H2O2, a ROS agonist) and EGF (an ERK agonist) promoted the cleavage of GSDME and caspase-3 in DDP or VP16 treatment cells, both of which were inhibited by HMGB1 knockdown. Importantly, these data were further supported by the in vivo experiment. Our study suggests that HMGB1 is a novel regulator of pyroptosis via the ROS/ERK1/2/caspase-3/GSDME pathway and a potential drug target for therapeutic interventions in neuroblastoma.
| S-EPMC9989614 | biostudies-literature
Project description: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.
| S-EPMC7884686 | biostudies-literature