Dextran sodium sulfate potentiates NLRP3 inflammasome activation by modulating the KCa3.1 potassium channel in a mouse model of colitis

Zeng, Bo; Huang, Yuanting; Chen, Siyuan; Xu, Rong; Xu, Lihui; Qiu, Jiahao; Shi, Fuli; Liu, Siying; Zha, Qing-Bing; Ouyang, Dong-Yun; He, Xian-Hui

doi:10.1038/s41423-022-00891-0

Cited by 26 publications

(11 citation statements)

References 68 publications

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“…However, the NLRP3 inflammasome is unlikely to be activated by ROS directly. NLRP3 can be activated by extracellular stimuli that induce K + efflux, such as ATP released from dying cells 46,57 . According to our results, aberrant ATP levels in the gastric mucosa of PHT models and PHG patients under hypoxic condition may be involved in NLRP3 inflammasome activation, gastric mucosal inflammation and lesion formation, and these effects could be reversed by HIF‐1α inhibition with PX‐478.…”

Section: Discussionsupporting

confidence: 51%

“…NLRP3 can be activated by extracellular stimuli that induce K + efflux, such as ATP released from dying cells. 46,57 According to our results, aberrant ATP levels in the gastric mucosa of PHT models and PHG patients under hypoxic condition may be involved in NLRP3 inflammasome activation, gastric mucosal inflammation and lesion formation, and these effects could be reversed by HIF-1α inhibition with PX-478. A decrease in mitochondrial membrane potential and increased intracellular Ca 2+ can also be NLRP3 activators that elicit a particular form of mitochondrial damage.…”

Section: F I G U R Ementioning

confidence: 67%

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Mitochondrial dysfunction induced by HIF‐1α under hypoxia contributes to the development of gastric mucosal lesions

Xiao,

Liu,

Xie

et al. 2024

Clinical & Translational Med

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IntroductionHypoxia is an important characteristic of gastric mucosal diseases, and hypoxia‐inducible factor‐1α (HIF‐1α) contributes to microenvironment disturbance and metabolic spectrum abnormalities. However, the underlying mechanism of HIF‐1α and its association with mitochondrial dysfunction in gastric mucosal lesions under hypoxia have not been fully clarified.ObjectivesTo evaluate the effects of hypoxia‐induced HIF‐1α on the development of gastric mucosal lesions.MethodsPortal hypertensive gastropathy (PHG) and gastric cancer (GC) were selected as representative diseases of benign and malignant gastric lesions, respectively. Gastric tissues from patients diagnosed with the above diseases were collected. Portal hypertension (PHT)‐induced mouse models in METTL3 mutant or NLRP3‐deficient littermates were established, and nude mouse gastric graft tumour models with relevant inhibitors were generated. The mechanisms underlying hypoxic condition, mitochondrial dysfunction and metabolic alterations in gastric mucosal lesions were further analysed.ResultsHIF‐1α, which can mediate mitochondrial dysfunction via upregulation of METTL3/IGF2BP3‐dependent dynamin‐related protein 1 (Drp1) N6‐methyladenosine modification to increase mitochondrial reactive oxygen species (mtROS) production, was elevated under hypoxic conditions in human and mouse portal hypertensive gastric mucosa and GC tissues. While blocking HIF‐1α with PX‐478, inhibiting Drp1‐dependent mitochondrial fission via mitochondrial division inhibitor 1 (Mdivi‐1) treatment or METTL3 mutation alleviated this process. Furthermore, HIF‐1α influenced energy metabolism by enhancing glycolysis via lactate dehydrogenase A. In addition, HIF‐1α‐induced Drp1‐dependent mitochondrial fission also enhanced glycolysis. Drp1‐dependent mitochondrial fission and enhanced glycolysis were associated with alterations in antioxidant enzyme activity and dysfunction of the mitochondrial electron transport chain, resulting in massive mtROS production, which was needed for activation of NLRP3 inflammasome to aggravate the development of the PHG and GC.ConclusionsUnder hypoxic conditions, HIF‐1α enhances mitochondrial dysfunction via Drp1‐dependent mitochondrial fission and influences the metabolic profile by altering glycolysis to increase mtROS production, which can trigger NLRP3 inflammasome activation and mucosal microenvironment alterations to contribute to the development of benign and malignant gastric mucosal lesions.

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Section: Discussionsupporting

confidence: 51%

Section: F I G U R Ementioning

confidence: 67%

Mitochondrial dysfunction induced by HIF‐1α under hypoxia contributes to the development of gastric mucosal lesions

Xiao,

Liu,

Xie

et al. 2024

Clinical & Translational Med

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“…For example, a study claims that DSS potentiates NLRP3 inflammasome activation by regulating the KCa3.1 potassium channel in a mouse model of colitis. This provides direct evidence for the role of pyroptosis in UC (39). In another study, the authors observed that Trans-10-Hydroxy-2-Decanoic acid could treat UC by inhibiting pyroptosis while also enhancing the barrier function of the colon (40).…”

Section: Discussionmentioning

confidence: 82%

Identification and exploration of pharmacological pyroptosis-related biomarkers of ulcerative colitis

Chen

Shang

et al. 2022

Front. Immunol.

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Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD). Its etiology is unclear. Much evidence suggests that the death of abnormal intestinal epithelial cells (IECs) leads to intestinal barrier disruption, and the subsequent inflammatory response plays a vital role in UC. Pyroptosis is a form of programmed inflammatory cell death, and the role of pyroptosis in UC etiology remains to be explored. This study identified 10 hub genes in pyroptosis by gene expression profiles obtained from the GSE87466 dataset. Meanwhile, the biomarkers were screened based on gene significance (GS) and module membership (MM) through the Weighted Gene Co-Expression Network Analysis (WGCNA). The following analysis indicated that hub genes were closely associated with the UC progression and therapeutic drug response. The single-cell RNA (scRNA) sequencing data from UC patients within the GSE162335 dataset indicated that macrophages were most related to pyroptosis. Finally, the expression of hub genes and response to the therapeutic drug [5-aminosalicylic acid (5-ASA)] were verified in dextran sulfate sodium (DSS)-induced colitis mice. Our study identified IL1B as the critical pyroptosis-related biomarker in UC. The crosstalk between macrophage pyroptosis and IEC pyroptosis may play an essential role in UC, deserving further exploration.

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“…First, the mouse model of ulcerative colitis was induced by dextran sulfate sodium salt (DSS) daily feeding. [23,34] Male Balb/c mice aged 6-8 weeks were randomly divided into six groups (n = 6). Healthy mice were used in the negative control group, and free MTX cocktail was used for the positive control group.…”

Section: In Vivo Anti-colitis Efficacy Evaluation Of the Mandsmentioning

confidence: 99%

Oral Administration of Multistage Albumin Nanomedicine Depots (MANDs) for Targeted Efficient Alleviation of Chronic Inflammatory Diseases

Zhang

Zheng

et al. 2023

Adv Funct Materials

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Methotrexate (MTX) by oral taking has been employed as the first‐line medication for various chronic inflammatory diseases treatment, such as Crohn's disease and rheumatoid arthritis (RA). However, the oral administration of MTX has very limited clinical benefits and will be discontinued due to the suboptimal response and severe adverse effects on intestinal mucosa. Herein, a multistage albumin nanomedicine depot (denoted as MAND) is formulated by encapsulating MTX‐loaded human serum albumin nanoparticles (MTX@HSA NPs) into calcium alginate chitosan microcapsules using a gas‐shearing technology. The MANDs can provide protection to MTX@HSA NPs with well‐persisted biologic activity against gastric acid erosion and realize specific boost release of MTX@HSA NPs in the intestinal tract in response to the mild basic circumstance. The MTX@HSA NPs absorbed by intestine can selectively accumulate in inflammation lesion by exploiting the inflammation targeting ability of HSA. In the animal experiments, the MANDs show improved therapeutic efficacy for the treatment of both RA and colitis with minimized intestinal side effects in respect to the free MTX by oral administration. Therefore, this conceived oral MANDs can promote a more clinic popularity and enhanced benefits of MTX for the treatment of chronic inflammatory diseases.

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Dextran sodium sulfate potentiates NLRP3 inflammasome activation by modulating the KCa3.1 potassium channel in a mouse model of colitis

Cited by 26 publications

References 68 publications

Mitochondrial dysfunction induced by HIF‐1α under hypoxia contributes to the development of gastric mucosal lesions

Mitochondrial dysfunction induced by HIF‐1α under hypoxia contributes to the development of gastric mucosal lesions

Identification and exploration of pharmacological pyroptosis-related biomarkers of ulcerative colitis

Oral Administration of Multistage Albumin Nanomedicine Depots (MANDs) for Targeted Efficient Alleviation of Chronic Inflammatory Diseases

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