ArticleThe Journal of clinical investigation2011
Activation of TNFR1 ectodomain shedding by mitochondrial Ca2+ determines the severity of inflammation in mouse lung microvessels.
Article in The Journal of clinical investigation, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
63 citing papers in PubMed, 1 synthesis or guideline pooled it, 104 citations in OpenAlex.
- Behҫet's Disease, and the Role of TNF-α and TNF-α Blockers.International journal of molecular sciences · 2020Pooled it
- Endothelial ADAM17 facilitates neutrophil migration and pulmonary microvascular permeability in acute lung inflammation.Journal of biomedical science · 2026Article
- Macrophage-specific therapy blocks the lung's mechanosensitive immune response to alveolar distension.JCI insight · 2025Article
- Bioactive Nanomaterials: Comprehensive Monitoring and Regulation of Acute Pancreatitis Induced Acute Lung Injury.International journal of nanomedicine · 2025Review
- Macrophage-specific lipid nanoparticle therapy blocks the lung's mechanosensitive immunity due to macrophage-epithelial interactions.bioRxiv : the preprint server for biology · 2024Article
- Studying the Pulmonary Endothelium in Health and Disease: An Official American Thoracic Society Workshop Report.American journal of respiratory cell and molecular biology · 2024Article
- Endothelial cell dynamics in sepsis-induced acute lung injury and acute respiratory distress syndrome: pathogenesis and therapeutic implications.Cell communication and signaling : CCS · 2024Review
- The rs11684747 and rs55790676 SNPs of ADAM17 influence tuberculosis susceptibility and plasma levels of TNF, TNFR1, and TNFR2.Frontiers in microbiology · 2024Article
- Mitochondria of lung venular capillaries mediate lung-liver cross talk in pneumonia.American journal of physiology. Lung cellular and molecular physiology · 2023Article
- Overview of the Mechanisms of Oxidative Stress: Impact in Inflammation of the Airway Diseases.Antioxidants (Basel, Switzerland) · 2022Review
- The mitochondrial calcium uniporter of pulmonary type 2 cells determines severity of acute lung injury.Nature communications · 2022Article
- Review
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- Salvianolic acid A regulates pyroptosis of endothelial cellsFrontiers in pharmacology · 2022Article
- Immune control of Mycobacterium tuberculosis is dependent on both soluble TNFRp55 and soluble TNFRp75.Immunology · 2021Article
- Oxidative Stress in Cancer Cell Metabolism.Antioxidants (Basel, Switzerland) · 2021Review
- Dantrolene repurposed to treat sepsis or septic shock and COVID-19 patients.European review for medical and pharmacological sciences · 2021Review
- Article
- Mitochondria Lead the Way: Mitochondrial Dynamics and Function in Cellular Movements in Development and Disease.Frontiers in cell and developmental biology · 2021Review
- Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Disease 2019.ERJ open research · 2020Review
3 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
Abstract
Shedding of the extracellular domain of cytokine receptors allows the diffusion of soluble receptors into the extracellular space; these then bind and neutralize their cytokine ligands, thus dampening inflammatory responses. The molecular mechanisms that control this process, and the extent to which shedding regulates cytokine-induced microvascular inflammation, are not well defined. Here, we used real-time confocal microscopy of mouse lung microvascular endothelium to demonstrate that mitochondria are key regulators of this process. The proinflammatory cytokine soluble TNF-α (sTNF-α) increased mitochondrial Ca2+, and the purinergic receptor P2Y2 prolonged the response. Concomitantly, the proinflammatory receptor TNF-α receptor-1 (TNFR1) was shed from the endothelial surface. Inhibiting the mitochondrial Ca2+ increase blocked the shedding and augmented inflammation, as denoted by increases in endothelial expression of the leukocyte adhesion receptor E-selectin and in microvascular leukocyte recruitment. The shedding was also blocked in microvessels after knockdown of a complex III component and after mitochondria-targeted catalase overexpression. Endothelial deletion of the TNF-α converting enzyme (TACE) prevented the TNF-α receptor shedding response, which suggests that exposure of microvascular endothelium to sTNF-α induced a Ca2+-dependent increase of mitochondrial H2O2 that caused TNFR1 shedding through TACE activation. These findings provide what we believe to be the first evidence that endothelial mitochondria regulate TNFR1 shedding and thereby determine the severity of sTNF-α-induced microvascular inflammation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.