ArticleInflammation research : official journal of the European Histamine Research Society ... [et al.]2022
Extracellular histones induce inflammation and senescence of vascular smooth muscle cells by activating the AMPK/FOXO4 signaling pathway.
Article in Inflammation research : official journal of the European Histamine Research Society ... [et al.], 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 16 citations in OpenAlex.
- Role of post-translational modifications in modulating histone reactivity in the extracellular environment.Biochemical Society transactions · 2026Review
- DAMP signaling networks: from receptors to diverse pathophysiological functions.Journal of advanced research · 2026Review
- Role of vascular smooth muscle cell pathobiology in sepsis‑induced vasoplegia (Review).International journal of molecular medicine · 2026Review
- Research status and molecular mechanisms of disulfidptosis in cardiovascular diseases (Review).Molecular medicine reports · 2026Review
- Research progress on the mechanism of FOXO protein in sepsis.Apoptosis : an international journal on programmed cell death · 2026Review
- Toll-like receptors in innate immunity and inflammation: from fundamental biology to clinic insights.Immunity & inflammation · 2026Review
- Pattern recognition receptors: function, regulation and therapeutic potential.Signal transduction and targeted therapy · 2025Review
- Sodium Tanshinone IIA Sulfonate alleviates vascular senescence in diabetic mice by modulating the A20-NFκB-NLRP3 inflammasome-catalase pathway.Scientific reports · 2024Article
- FGF21 overexpression alleviates VSMC senescence in diabetic mice by modulating the SYK-NLRP3 inflammasome-PPARγ-catalase pathway.Acta biochimica et biophysica Sinica · 2024Article
- PAMPs and DAMPs in Sepsis: A Review of Their Molecular Features and Potential Clinical Implications.International journal of molecular sciences · 2024Review
- Emerging therapeutic strategies targeting extracellular histones for critical and inflammatory diseases: an updated narrative review.Frontiers in immunology · 2024Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundSepsis is an abnormal immune-inflammatory response that is mainly caused by infection. It can lead to life-threatening organ dysfunction and death. Severely damaged tissue cells will release intracellular histones into the circulation as damage-related molecular patterns (DAMPs) to accelerate the systemic immune response. Although various histone-related cytotoxicity mechanisms have been explored, those that affect extracellular histones involved in vascular smooth muscle cell (VSMC) dysfunction are yet to be determined.
methodsMouse aortic vascular smooth muscle cells (VSMCs) were stimulated with different concentrations of histones, and cell viability was detected by CCK-8 assay. Cellular senescence was assessed by SA β-gal staining. C57BL/6 mice were treated with histones with or without BML-275 treatment. RT-qPCR was performed to determine the expression of inflammatory cytokines. Western blotting was used to analyze the expression of NLRP3, ASC and caspase-1 inflammasome proteins. The interaction of NLRP3 and ASC was detected by CoIP and immunofluorescence staining.
resultsIn this study, we found that extracellular histones induced senescence and inflammatory response in a dose-dependent manner in cultured VSMCs. Histone treatment significantly promoted apoptosis-associated speck-like protein containing CARD (ASC) as well as NACHT, LRR and PYD domains-containing protein 3 (NLRP3) interaction of inflammasomes in VSMCs. Forkhead box protein O4 (FOXO4), which is a downstream effector molecule of extracellular histones, was found to be involved in histone-regulated VSMC inflammatory response and senescence. Furthermore, the 5'-AMP-activated protein kinase (AMPK) signaling pathway was confirmed to mediate extracellular histone-induced FOXO4 expression, and blocking this signaling pathway with an inhibitor can suppress vascular inflammation induced by extracellular histones in vivo and in vitro.
conclusionExtracellular histones induce inflammation and senescence in VSMCs, and blocking the AMPK/FOXO4 pathway is a potential target for the treatment of histonemediated organ injury.
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