ArticleCellular & molecular immunology2024
MLKL-mediated endothelial necroptosis drives vascular damage and mortality in systemic inflammatory response syndrome.
Article in Cellular & molecular immunology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- DDX3x Regulates NINJ1 Transcription via Histone Lactylation in Sepsis Associated-Acute Kidney Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Staphylococcus aureus-vascular endothelium interactions: Mechanisms and therapeutic opportunities.European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology · 2026Review
- Multiple organ dysfunction syndrome: molecular mechanisms and therapeutic strategies.Signal transduction and targeted therapy · 2026Review
- Angiocrine factors in tumor microenvironment: bidirectional crosstalk, mechanistic insights, and therapeutic strategies.Journal of translational medicine · 2026Review
- Necroptosis in alveolar epithelium orchestrates lung ischemia-reperfusion injury: a multi-omics study.Respiratory research · 2026Article
- Necroptosis is a key contributor to impaired cardiac repair following myocardial infarction.Cell death & disease · 2026Article
- Article
- Regulated cell death: a multidimensional regulatory network in the pathogenesis of renal fibrosis.Apoptosis : an international journal on programmed cell death · 2026Review
- Cumulative stress hyperglycemia ratio exposure and dynamic trajectories reveal prognostic determinants of acute hyperlipidemic pancreatitis: an 5-year cohort study.Lipids in health and disease · 2026Article
- The predictive value of platelet-to-lymphocyte ratio and lymphocyte count in recurrent small intestinal hemorrhage: a retrospective cohort study.BMC gastroenterology · 2026Article
- Prognostic Value of a Composite Inflammation-Renal Function Score in Type A Aortic Dissection.Journal of cardiovascular development and disease · 2026Article
- Multicellular Model Reveals the Mechanism of AEE Alleviating Vascular Endothelial Cell Injury via Anti-Inflammatory and Antioxidant Effects.International journal of molecular sciences · 2026Article
- Iron-dependent ferroptosis in cardiac microvascular endothelial cells: a key link between dysregulated iron homeostasis and microcirculatory injury during myocardial ischemia-reperfusion.Frontiers in cardiovascular medicine · 2026Review
- Remodeling the tumor immune microenvironment: mechanisms of crosstalk between regulated cell death macrophages.Frontiers in immunology · 2026Review
- Cell death mechanisms in heat stroke and sepsis: ZBP1 and caspase-11 as molecular sensors driving the MLKL/GSDMD death execution axis.Frontiers in cell and developmental biology · 2026Review
- Necroptotic cell death consequences and disease relevance.Nature immunology · 2025Review
- Role of RIPK1/RIPK3/MLKL signalling pathway in sepsis-associated acute kidney injury.Experimental physiology · 2025Review
- Research advances on the role of programmed endothelial cell death in sepsis.Cell death discovery · 2025Review
- Cumulative intra-abdominal pressure exposure and dynamic trajectories in ICU-admitted patients reveal prognostic determinants of severe acute pancreatitis.World journal of emergency surgery : WJES · 2025Article
- Opposing regulation of the K63-linked polyubiquitination of RIPK3 by SMURF1 and USP5 in necroptosis.Nature communications · 2025Article
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Authors and funding
24 authors.
Funding
Abstract
The hypersecretion of cytokines triggers life-threatening systemic inflammatory response syndrome (SIRS), leading to multiple organ dysfunction syndrome (MODS) and mortality. Although both coagulopathy and necroptosis have been identified as important factors in the pathogenesis of SIRS, the specific cell types that undergo necroptosis and the interrelationships between coagulopathy and necroptosis remain unclear. In this study, we utilized visualization analysis via intravital microscopy to demonstrate that both anticoagulant heparin and nonanticoagulant heparin (NAH) pretreatment protect mice against TNF-α-induced mortality in SIRS. Moreover, the deletion of Mlkl or Ripk3 resulted in decreased coagulation and reduced mortality in TNF-α-induced SIRS. These findings suggest that necroptosis plays a key role upstream of coagulation in SIRS-related mortality. Furthermore, using a genetic lineage tracing mouse model (Tie2-Cre;Rosa26-tdT), we tracked endothelial cells (ECs) and verified that EC necroptosis is responsible for the vascular damage observed in TNF-α-treated mice. Importantly, Mlkl deletion in vascular ECs in mice had a similar protective effect against lethal SIRS by blocking EC necroptosis to protect the integrity of the endothelium. Collectively, our findings demonstrated that RIPK3-MLKL-dependent necroptosis disrupted vascular integrity, resulting in coagulopathy and multiorgan failure, eventually leading to mortality in SIRS patients. These results highlight the importance of targeting vascular EC necroptosis for the development of effective treatments for SIRS patients.
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