Pyroptosis in NLRP3 inflammasome-related atherosclerosis

Zeng, Xiang; Liu, Dongling; Huo, Xia; Wu, Yue; Liu, Cuiqing; Sun, Qinghua

doi:10.15698/cst2022.10.272

Cited by 9 publications

(3 citation statements)

References 111 publications

(142 reference statements)

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“…NLRP3 is the best-characterized type of inflammasome [ 16 ]. Assemblage of NLRP3, ASC, and procaspase triggers NLRP3 inflammasome activation [ 17 ]. The active inflammasome then recruits and activates caspase-1, which is followed by the cleavage and subsequent activation of proinflammatory cytokines such as IL-1β and IL-18, resulting in pyroptosis [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Adrenomedullin Mitigates Doxorubicin-Induced Nephrotoxicity in Rats: Role of Oxidative Stress, Inflammation, Apoptosis, and Pyroptosis

Abdellatif

Nasef

El‐Horany

et al. 2022

IJMS

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Doxorubicin (DOX) is an anticancer antibiotic which has various effects in human cancers. It is one of the commonly known causes of drug-induced nephrotoxicity, which results in acute renal injury. Adrenomedullin (ADM), a vasodilator peptide, is widely distributed in many tissues and has potent protective effects. Therefore, the current study aimed to examine the protective potential mechanisms of ADM against DOX-induced nephrotoxicity. A total of 28 male Wistar rats were randomized into four groups: control group, doxorubicin group (15 mg/kg single intraperitoneal injection of DOX), adrenomedullin + doxorubicin group (12 μg/kg/day intraperitoneal injection of ADM) 3 days prior to DOX injection and continuing for 14 days after the model was established, and adrenomedullin group. Kidney function biomarkers, oxidative stress markers, and inflammatory mediators (TNF-α, NLRP3, IL-1β, and IL-18) were assessed. The expressions of gasdermin D and ASC were assessed by real-time PCR. Furthermore, the abundances of caspase-1 (p20), Bcl-2, and Bax immunoreactivity were evaluated. ADM administration improved the biochemical parameters of DOX-induced nephrotoxicity, significantly reduced oxidative damage markers and inflammatory mediators, and suppressed both apoptosis and pyroptosis. These results were confirmed by the histopathological findings and revealed that ADM’s antioxidant, anti-inflammatory, anti-apoptotic, and anti-pyroptotic properties may have prospective applications in the amelioration of DOX-induced nephrotoxicity.

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Section: Introductionmentioning

confidence: 99%

Adrenomedullin Mitigates Doxorubicin-Induced Nephrotoxicity in Rats: Role of Oxidative Stress, Inflammation, Apoptosis, and Pyroptosis

Abdellatif

Nasef

El‐Horany

et al. 2022

IJMS

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“…Lipids serve as essential building blocks for cells and are an important energy source for microglia 49 , but they also have the potential to act as pro-inflammatory stimuli. Excessive cellular accumulation of lipids can lead to toxicity and trigger apoptosis, emphasizing the delicate balance required for maintaining cellular health 69,70 .…”

Section: Discussionmentioning

confidence: 99%

Loss of CLN3 in microglia leads to impaired lipid metabolism and myelin turnover

Yasa,

Butz,

Colombo

et al. 2024

Preprint

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Background: Microglia are the primary brain cell type regulating neuroinflammation and they are important for healthy aging. Genes regulating microglial function are associated with an increased risk of neurodegenerative disease. Loss-of-function mutations in CLN3, which encodes an endolysosomal membrane protein, lead to the most common childhood-onset form of neurodegeneration, featuring early-stage neuroinflammation that long precedes neuronal cell loss. How loss of CLN3 function leads to this early neuroinflammation is not yet understood. Methods: Here, we have comprehensively studied microglia from Cln3∆ex7/8 mice, a genetically accurate CLN3 disease model. Microglia were isolated from young and old Cln3∆ex7/8 mice for downstream molecular and functional studies. Results: We show that loss of CLN3 function in microglia leads to classic age-dependent CLN3-disease lysosomal storage as well as an altered morphology of the lysosome, mitochonodria and Golgi compartments. Consistent with these morphological alterations, we also discovered pathological proteomic signatures implicating defects in lysosomal function and lipid metabolism processes at an early disease stage. CLN3-deficient microglia were unable to efficiently turnover myelin and metabolize its associated lipids, showing severe defects in lipid droplet formation and significant accumulation of cholesterol, phenotypes that were corrected by treatment with autophagy inducers and cholesterol lowering drugs. Finally, we observed reduced myelination in aging homozygous Cln3∆ex7/8 mice suggesting altered myelin turnover by microglia impacts myelination in the CLN3-deficient brain. Conclusion: Our results implicate a cell autonomous defect in CLN3-deficient microglia that impacts the ability of these cells to support neuronal cell health. These results strongly suggest microglial targeted therapies should be considered for CLN3 disease.

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“…20) Moreover, the induction of pyroptosis is closely linked to the activation of the NODlike receptor protein 3 (NLRP3) inflammasome, a key risk factor for several cardiovascular inflammation disease development. 21,22) For example, silencing NLRP3 ameliorates diabetic rats' cardiac inflammation and pyroptosis, improving myocardial function. 23) Meanwhile, cathepsin B aggravates viral myocarditis caused by coxsackievirus B3 through NLRP3 inflammasome activation, leading to pyroptosis.…”

mentioning

confidence: 99%

Role of CCRL2 in the Pathogenesis of Experimental Autoimmune Myocarditis via P21-Activated Kinase 1/NOD-Like Receptor Protein 3 Pathway

Chen,

Meng,

Zheng

et al. 2024

Int. Heart J.

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Myocarditis, a severe inflammatory disease, is becoming a worldwide public health concern. This study aims to elucidate the effect of Chemokine (C C motif) receptor-like 2 (CCRL2) in experimental autoimmune myocarditis (EAM) occurrence and its potential regulatory mechanisms.EAM was simulated in a mouse model injected with α-myosin-heavy chain. The changes on EAM were assessed through histological staining of heart tissues, including measuring cardiac troponin I (cTnI), proinflammatory cytokines, transferase-mediated dUTP nick end labeling (TUNEL) assay, and cardiac function. Then, the heart tissues from the EAM mouse model and control groups were analyzed through transcriptome sequencing to identify the differential expressed genes (DEGs) and hub genes related to pyroptosis. Downregulation of CCRL2 further verified the function of CCRL2 on EAM and p21-activated kinase 1/NOD-like receptor protein 3 (PAK/NLRP3) signaling pathways in vivo.The EAM model was constructed successfully, with the heart weight/body weight ratio, serum level of cTnI, and concentrations of proinflammatory cytokines elevation. Moreover, cell apoptosis was also significantly increased. Transcriptome sequencing revealed 696 and 120 upregulated and downregulated DEGs, respectively. After functional enrichment, CCRL2 was selected as a potential target. Then, we verified that CCRL2 knockdown improved cardiac function, alleviated EAM occurrence, and reduced PAK/NLRP3 protein expression.CCRL2 may act as a novel potential treatment target in EAM by regulating the PAK1/NLRP3 pathway.

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Pyroptosis in NLRP3 inflammasome-related atherosclerosis

Cited by 9 publications

References 111 publications

Adrenomedullin Mitigates Doxorubicin-Induced Nephrotoxicity in Rats: Role of Oxidative Stress, Inflammation, Apoptosis, and Pyroptosis

Adrenomedullin Mitigates Doxorubicin-Induced Nephrotoxicity in Rats: Role of Oxidative Stress, Inflammation, Apoptosis, and Pyroptosis

Loss of CLN3 in microglia leads to impaired lipid metabolism and myelin turnover

Role of CCRL2 in the Pathogenesis of Experimental Autoimmune Myocarditis via P21-Activated Kinase 1/NOD-Like Receptor Protein 3 Pathway

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