Caspase-1-Inhibitor AC-YVAD-CMK Inhibits Pyroptosis and Ameliorates Acute Kidney Injury in a Model of Sepsis

Yang, Mei; Fang, Jintao; Zhang, Ni-Shang; Qin, Longjiang; Yangyang, Zhuang; Wang, Weiwei; Zhu, Haiping; Zhang, Yanjie; Xia, Peng

doi:10.1155/2021/6636621

Cited by 24 publications

(14 citation statements)

References 43 publications

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“…Neutrophil pyroptosis is a pro-inflammatory process mediated by GSDMD (Wen et al, 2022). Yang et al showed that neutrophils could secrete IL-1b through a CASP1dependent pathway, resulting in a higher mortality rate in mice (Yang et al, 2021). Sepsis could cause immune dysregulation and suppression of adaptive immune cells.…”

Section: Discussionmentioning

confidence: 99%

Significant difference of differential expression pyroptosis-related genes and their correlations with infiltrated immune cells in sepsis

Wang

Zhang

et al. 2022

Front. Cell. Infect. Microbiol.

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BackgroundSepsis is regarded as a life-threatening organ dysfunction syndrome that responds to infection. Pyroptosis, a unique form of programmed cell death, is characterized by inflammatory cytokine secretion. Recently, an increasing number of studies have investigated the relationship between sepsis and pyroptosis. Appropriate pyroptosis can help to control infection during sepsis, but an immoderate one may cause immune disorders. The present study aimed to identify pyroptosis-related gene biomarkers and their relationship with the immune microenvironment using the genome-wide technique.MethodsThe training dataset GSE154918 and the validation dataset GSE185263 were downloaded for bioinformatics analysis. Differentially expressed pyroptosis-related genes (DEPRGs) were identified between sepsis (including septic shock) and healthy samples. Gene Set Enrichment Analysis (GSEA) was performed to explore gene function. CIBERSORT tools were applied to quantify infiltrating immune cells, and the correlation between differentially infiltrating immune cells and DEPRG expression was investigated. Furthermore, based on multivariable Cox regression, the study also utilized a random forest (RF) model to screen biomarkers.ResultsIn total, 12 DEPRGs were identified. The expression level of PLCG1 was continuously significantly decreased, while the expression level of NLRC4 was elevated from control to sepsis and then to septic shock. GSEA found that one DEPRG (PLCG1) was involved in the T-cell receptor signaling pathway and that many T cell-related immunologic signature gene sets were enriched. The proportions of plasma cells, T cells CD4 memory activated, and some innate cells in the sepsis group were significantly higher than those in the healthy group, while the proportions of T cells CD8, T cells CD4 memory resting, T cells regulatory (Tregs), and NK cells were lower. Additionally, CASP4 was positively correlated with Neutrophils and negatively correlated with T cells CD4 memory resting and Tregs. Lastly, two biomarkers (CASP4 and PLCG1) were identified, and a nomogram model was constructed for diagnosis with area under the curve (AUC) values of 0.998.ConclusionThis study identified two potential pyroptosis-related diagnostic genes, CASP4 and PLCG1, and explored the correlation between DEPRGs and the immune microenvironment. Also, our study indicated that some DEPRGs were satisfactorily correlated with several representative immune cells that can regulate pyroptosis.

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Section: Discussionmentioning

confidence: 99%

Significant difference of differential expression pyroptosis-related genes and their correlations with infiltrated immune cells in sepsis

Wang

Zhang

et al. 2022

Front. Cell. Infect. Microbiol.

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“…However, the release of pro-inflammatory cytokine IL-1β appears to exacerbate the pro-inflammatory response and the spread of local tissue damage, which has been confirmed in a murine model of melioidosis ( 102 , 103 ). It was reported that IL-1β can be released by pyroptosis via the classical pathway, which lowers the murine survival rates ( 104 ). However, in 2014, Chen et al.…”

Section: Pyroptosismentioning

confidence: 99%

Dysregulation of neutrophil death in sepsis

et al. 2022

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Sepsis is a prevalent disease that has alarmingly high mortality rates and, for several survivors, long-term morbidity. The modern definition of sepsis is an aberrant host response to infection followed by a life-threatening organ dysfunction. Sepsis has a complicated pathophysiology and involves multiple immune and non-immune mediators. It is now believed that in the initial stages of sepsis, excessive immune system activation and cascading inflammation are usually accompanied by immunosuppression. During the pathophysiology of severe sepsis, neutrophils are crucial. Recent researches have demonstrated a clear link between the process of neutrophil cell death and the emergence of organ dysfunction in sepsis. During sepsis, spontaneous apoptosis of neutrophils is inhibited and neutrophils may undergo some other types of cell death. In this review, we describe various types of neutrophil cell death, including necrosis, apoptosis, necroptosis, pyroptosis, NETosis, and autophagy, to reveal their known effects in the development and progression of sepsis. However, the exact role and mechanisms of neutrophil cell death in sepsis have not been fully elucidated, and this remains a major challenge for future neutrophil research. We hope that this review will provide hints for researches regarding neutrophil cell death in sepsis and provide insights for clinical practitioners.

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“…Recent research has confirmed the high expression of the active forms of caspase-1, GSDMD and inflammatory cytokines IL-1β and IL-18 in primary human TECs and LPS-induced mouse kidneys ( 107 ). The use of caspase-1 inhibitors can reduce the expression of NLRP1 inflammasome and the pyroptosis of TECs ( 108 ). By employing genetic and pharmacological methods, targeting the pyroptosis pathway can effectively reduce the expression and function of NLRP3 and GSDMD in sepsis-AKI ( 107 , 109 – 111 ).…”

Section: Types Of Programmed Cell Death In Sepsis-akimentioning

confidence: 99%

The Programmed Cell Death of Macrophages, Endothelial Cells, and Tubular Epithelial Cells in Sepsis-AKI

Wang

et al. 2021

Front. Med.

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Sepsis is a systemic inflammatory response syndrome caused by infection, following with acute injury to multiple organs. Sepsis-induced acute kidney injury (AKI) is currently recognized as one of the most severe complications related to sepsis. The pathophysiology of sepsis-AKI involves multiple cell types, including macrophages, vascular endothelial cells (ECs) and renal tubular epithelial cells (TECs), etc. More significantly, programmed cell death including apoptosis, necroptosis and pyroptosis could be triggered by sepsis in these types of cells, which enhances AKI progress. Moreover, the cross-talk and connections between these cells and cell death are critical for better understanding the pathophysiological basis of sepsis-AKI. Mitochondria dysfunction and oxidative stress are traditionally considered as the leading triggers of programmed cell death. Recent findings also highlight that autophagy, mitochondria quality control and epigenetic modification, which interact with programmed cell death, participate in the damage process in sepsis-AKI. The insightful understanding of the programmed cell death in sepsis-AKI could facilitate the development of effective treatment, as well as preventive methods.

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Caspase-1-Inhibitor AC-YVAD-CMK Inhibits Pyroptosis and Ameliorates Acute Kidney Injury in a Model of Sepsis

Cited by 24 publications

References 43 publications

Significant difference of differential expression pyroptosis-related genes and their correlations with infiltrated immune cells in sepsis

Significant difference of differential expression pyroptosis-related genes and their correlations with infiltrated immune cells in sepsis

Dysregulation of neutrophil death in sepsis

The Programmed Cell Death of Macrophages, Endothelial Cells, and Tubular Epithelial Cells in Sepsis-AKI

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