Neutrophil Extracellular Traps Induce Glomerular Endothelial Cell Dysfunction and Pyroptosis in Diabetic Kidney Disease

Zheng, Fengfan; Ma, Linqiang; Li, Xuan; Gao, Rufei; Peng, Chuan; Kang, Bing; Wang, Yue; Luo, Ting; Wu, Jinshan; Yang, Yi; Gong, Lilin; Li, Qifu; Hu, Jinbo

doi:10.2337/db22-0153

Cited by 27 publications

(27 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2 ). More limited evidence supports a role for mitochondrial permeability transition-regulated necrosis (MPT-RN), autosis and NETosis (derived from the term neutrophil extracellular traps (NETs)) in the pathogenesis of kidney disease 18 – 28 . However, much work is needed to understand the relative contribution of the diverse forms of regulated necrosis to human kidney disease, the extent to which the pathways are interconnected and the extent to which they can be targeted therapeutically.…”

Section: Introductionmentioning

confidence: 99%

Regulated cell death pathways in kidney disease

et al. 2023

View full text Add to dashboard Cite

Disorders of cell number that result from an imbalance between the death of parenchymal cells and the proliferation or recruitment of maladaptive cells contributes to the pathogenesis of kidney disease. Acute kidney injury can result from an acute loss of kidney epithelial cells. In chronic kidney disease, loss of kidney epithelial cells leads to glomerulosclerosis and tubular atrophy, whereas interstitial inflammation and fibrosis result from an excess of leukocytes and myofibroblasts. Other conditions, such as acquired cystic disease and kidney cancer, are characterized by excess numbers of cyst wall and malignant cells, respectively. Cell death modalities act to clear unwanted cells, but disproportionate responses can contribute to the detrimental loss of kidney cells. Indeed, pathways of regulated cell death — including apoptosis and necrosis — have emerged as central events in the pathogenesis of various kidney diseases that may be amenable to therapeutic intervention. Modes of regulated necrosis, such as ferroptosis, necroptosis and pyroptosis may cause kidney injury directly or through the recruitment of immune cells and stimulation of inflammatory responses. Importantly, multiple layers of interconnections exist between different modalities of regulated cell death, including shared triggers, molecular components and protective mechanisms.

show abstract

Section: Introductionmentioning

confidence: 99%

Regulated cell death pathways in kidney disease

et al. 2023

View full text Add to dashboard Cite

show abstract

“…And the excessive release of NETs in lung tissue has been reported to induce macrophage pyroptosis ( 12 , 13 ). This inflammatory cell death will further amplify the inflammatory response, thus making it difficult to control the disease process ( 28 , 29 ). In this study, we demonstrate a previously unidentified role of Pyrin inflammasome in driving NETs-induced macrophage pyroptosis.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, animal experiments also found that, in the sepsis model, the level of NETs in the BALF of mice also increased significantly ( 32 ), and the increased level of NETs was related to the proportion of pyroptosis of alveolar macrophages ( 13 ). Using DNase I(An endonuclease that digests DNA) to inhibit the generation of NETs could significantly reduce cell pyroptosis, thereby reducing the inflammatory response and improving the survival rate ( 28 ). In this study, we also found that the level of alveolar NETs was significantly increased in the sepsis mice model, and the extent of pyroptosis in lung tissue was increased significantly.…”

Section: Discussionmentioning

confidence: 99%

Alpha-linolenic acid pretreatment alleviates NETs-induced alveolar macrophage pyroptosis by inhibiting pyrin inflammasome activation in a mouse model of sepsis-induced ALI/ARDS

Liu

Zhou

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

BackgroundNeutrophil extracellular traps (NETs) can cause acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) by inducing macrophage pyroptosis. The purpose of this study was to find out whether pretreatment of alpha-linolenic acid (ALA) could inhibit NETs-induced macrophage pyroptosis in sepsis-induced ALI/ARDS, as well as to identify which inflammasome is involved in this process.MethodsLPS was instilled into the trachea to establish sepsis-induced ALI/ARDS in a mouse model. Lung injury was assessed by microscopic examination of lung tissue after hematoxylin and eosin staining, pathology score, and bronchoalveolar lavage fluid (BALF) total protein concentration. The level of NETs in lung tissue was detected by MPO-DNA ELISA. Purified NETs, extracted from peritoneal neutrophils, induced macrophage pyroptosis in vitro. Expression of pyroptosis-related proteins (Cl-caspase-1, Cl-GSDMD, ASC) and IL-1β in the lung tissue and bone marrow-derived macrophages (BMDMs) were determined by western blotting or ELISA. Specks of Pyrin/ASC were examined by confocal immunofluorescence microscopy. Mefv (Pyrin)-/- mice were used to study the role of Pyrin in the process of sepsis-induced ALI/ARDS.ResultsALA alleviated LPS-induced lung injury. ALA reduced the level of NETs, pyroptosis-related proteins (Cl-caspase-1, Cl-GSDMD, ASC), and IL-1β in the lung tissue of sepsis mice. In vitro, NETs increased the expression of pyroptosis-related proteins (Cl-caspase-1, Cl-GSDMD, ASC) and IL-1β significantly in BMDMs. Pyrin protein was found to be higher and form the inflammasome with ASC in NETs challenged-BMDMs. Knockout of Mefv (Pyrin) gene fully restored the increased expression of pyroptosis-related proteins (Cl-caspase-1, Cl-GSDMD, ASC) and IL-1β in vitro and in vivo. Lung injury was alleviated significantly in Mefv (Pyrin)-/- mice as well. ALA suppresses all the NETs-induced changes as mentioned above.ConclusionOur study is the first to demonstrate Pyrin inflammasome driving NETs-induced macrophage pyroptosis, and ALA may reduce ALI/ARDS by inhibiting the activation of the Pyrin inflammasome-driven macrophage pyroptosis.

show abstract

“…NETs can increase the metastatic potential of circulating tumor cells through augmentation of cell cycle progression (14). Hu et al reported that NETs could promote the dysfunction of glomerular endothelial cells and pyroptosis in diabetic kidney disease (15). NETs are closely associated with dirty necrosis in RCC (16).…”

Section: Introductionmentioning

confidence: 99%

“…Hu et al. reported that NETs could promote the dysfunction of glomerular endothelial cells and pyroptosis in diabetic kidney disease ( 15 ). NETs are closely associated with dirty necrosis in RCC ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

Neutrophil extracellular traps-associated modification patterns depict the tumor microenvironment, precision immunotherapy, and prognosis of clear cell renal cell carcinoma

Teng

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

BackgroundNeutrophil extracellular traps (NETs) are web-like structures formed by neutrophils, and their main function is antimicrobial defense. Moreover, NETs have numerous roles in the pathogenesis and progression of cancers. However, the potential roles of NET-related genes in renal cell carcinoma remain unclear. In this study, we comprehensively investigated the NETs patterns and their relationships with tumor environment (TME), clinicopathological features, prognosis, and prediction of therapeutic benefits in the clear cell renal cell carcinoma (ccRCC) cohort.MethodsWe obtained the gene expression profiles, clinical characteristics, and somatic mutations of patients with ccRCC from The Cancer Genome Atlas database (TCGA), Gene Expression Omnibus (GEO), and ArrayExpress datasets, respectively. ConsensusCluster was performed to identify the NET clusters. The tumor environment scores were evaluated by the “ESTIMATE,” “CIBERSORT,” and ssGSEA methods. The differential analysis was performed by the “limma” R package. The NET-scores were constructed based on the differentially expressed genes (DEGs) among the three cluster patterns using the ssGSEA method. The roles of NET scores in the prediction of immunotherapy were investigated by Immunophenoscores (TCIA database) and validated in two independent cohorts (GSE135222 and IMvigor210). The prediction of targeted drug benefits was implemented using the “pRRophetic” and Gene Set Cancer Analysis (GSCA) datasets. Real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) was performed to identify the reliability of the core genes’ expression in kidney cancer cells.ResultsThree NET-related clusters were identified in the ccRCC cohort. The patients in Cluster A had more metabolism-associated pathways and better overall survival outcomes, whereas the patients in Cluster C had more immune-related pathways, a higher immune score, and a poorer prognosis than those in Cluster B. Based on the DEGs among different subtypes, patients with ccRCC were divided into two gene clusters. These gene clusters demonstrated significantly different immune statuses and clinical features. The NET scores were calculated based on the ten core genes by the Gene Set Variation Analysis (GSVA) package and then divided ccRCC patients into two risk groups. We observed that high NET scores were associated with favorable survival outcomes, which were validated in the E-MTAB-1980 dataset. Moreover, the NET scores were significantly associated with immune cell infiltration, targeted drug response, and immunotherapy benefits. Subsequently, we explored the expression profiles, methylation, mutation, and survival prediction of the 10 core genes in TCGA-KIRC. Though all of them were associated with survival information, only four out of the 10 core genes were differentially expressed genes in tumor samples compared to normal tissues. Finally, RT-PCR showed that MAP7, SLC16A12, and SLC27A2 decreased, while SLC3A1 increased, in cancer cells.ConclusionNETs play significant roles in the tumor immune microenvironment of ccRCC. Identifying NET clusters and scores could enhance our understanding of the heterogeneity of ccRCC, thus providing novel insights for precise individual treatment.

show abstract

Neutrophil Extracellular Traps Induce Glomerular Endothelial Cell Dysfunction and Pyroptosis in Diabetic Kidney Disease

Cited by 27 publications

References 44 publications

Regulated cell death pathways in kidney disease

Regulated cell death pathways in kidney disease

Alpha-linolenic acid pretreatment alleviates NETs-induced alveolar macrophage pyroptosis by inhibiting pyrin inflammasome activation in a mouse model of sepsis-induced ALI/ARDS

Neutrophil extracellular traps-associated modification patterns depict the tumor microenvironment, precision immunotherapy, and prognosis of clear cell renal cell carcinoma

Contact Info

Product

Resources

About