ArticlePLoS pathogens2015
Pore-Forming Toxins Induce Macrophage Necroptosis during Acute Bacterial Pneumonia.
Article in PLoS pathogens, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 149 papers, 1 of them a synthesis that pooled it.
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Who cites it
149 citing papers in PubMed, 1 synthesis or guideline pooled it, 227 citations in OpenAlex.
- Pneumolysin as a target for new therapies against pneumococcal infections: A systematic review.PloS one · 2023Pooled it
- Impact of macrolide treatment on long-term mortality in patients admitted to the ICU due to CAP: a targeted maximum likelihood estimation and survival analysis.Critical care (London, England) · 2023Trial
- Phage-Antibiotic-Peptide Synergy Overcomes Biofilm-Mediated Multidrug Resistance inAntibiotics (Basel, Switzerland) · 2026Article
- Extracellular pneumolysin enhances the activation of cytosolic pattern-recognition receptor NOD2 through its pore-forming activity.Microbiology spectrum · 2026Article
- The signaling and regulatory functions of dying cells and cell corpses.Communications biology · 2026Review
- Immune pathways that regulate neutrophil activation and replenishment prevent persistent pneumococcal colonization.PLoS pathogens · 2026Article
- A Triple-Modality Peptide-Antibiotic-Phage Therapy Eradicates Multidrug-ResistantbioRxiv : the preprint server for biology · 2026Article
- Bacterial pore-forming toxins: mechanisms and implications for host immunity.Bioscience reports · 2026Review
- Immune pathways that regulate neutrophil activation and replenishment prevent persistent pneumococcal colonization.bioRxiv : the preprint server for biology · 2026Article
- Article
- Apoptosis as an evolutionary battleground: pathogen pressure and the shaping of programmed cell death pathways.Frontiers in cell and developmental biology · 2026Review
- Targeting PANoptosis: a promising therapeutic strategy for ALI/ARDS.Apoptosis : an international journal on programmed cell death · 2025Review
- Cell death signaling and immune regulation: new perspectives on targeted therapy for sepsis.Cellular & molecular biology letters · 2025Review
- The Multifaceted Role of Calcium Signaling in Regulated Necrosis.Biomolecules · 2025Review
- Caspase-1-licensed pyroptosis drives dsRNA-mediated necroptosis and dampens host defense against bacterial pneumonia.PLoS pathogens · 2025Article
- Article
- Targeting alveolar epithelial cells with lipid micelle-encapsulated necroptosis inhibitors to alleviate acute lung injury.Communications biology · 2025Article
- Phagocytosis by macrophages decreases the radiance of bioluminescent Staphylococcus aureus.BMC microbiology · 2025Article
- Regulated programmed cell death in acute lung injury: from pathogenesis to therapy.Frontiers in immunology · 2025Review
- Cell death in acute lung injury: caspase-regulated apoptosis, pyroptosis, necroptosis, and PANoptosis.Frontiers in pharmacology · 2025Review
89 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Necroptosis is a highly pro-inflammatory mode of cell death regulated by RIP (or RIPK)1 and RIP3 kinases and mediated by the effector MLKL. We report that diverse bacterial pathogens that produce a pore-forming toxin (PFT) induce necroptosis of macrophages and this can be blocked for protection against Serratia marcescens hemorrhagic pneumonia. Following challenge with S. marcescens, Staphylococcus aureus, Streptococcus pneumoniae, Listeria monocytogenes, uropathogenic Escherichia coli (UPEC), and purified recombinant pneumolysin, macrophages pretreated with inhibitors of RIP1, RIP3, and MLKL were protected against death. Alveolar macrophages in MLKL KO mice were also protected during S. marcescens pneumonia. Inhibition of caspases had no impact on macrophage death and caspase-1 and -3/7 were determined to be inactive following challenge despite the detection of IL-1β in supernatants. Bone marrow-derived macrophages from RIP3 KO, but not caspase-1/11 KO or caspase-3 KO mice, were resistant to PFT-induced death. We explored the mechanisms for PFT-induced necroptosis and determined that loss of ion homeostasis at the plasma membrane, mitochondrial damage, ATP depletion, and the generation of reactive oxygen species were together responsible. Treatment of mice with necrostatin-5, an inhibitor of RIP1; GW806742X, an inhibitor of MLKL; and necrostatin-5 along with co-enzyme Q10 (N5/C10), which enhances ATP production; reduced the severity of S. marcescens pneumonia in a mouse intratracheal challenge model. N5/C10 protected alveolar macrophages, reduced bacterial burden, and lessened hemorrhage in the lungs. We conclude that necroptosis is the major cell death pathway evoked by PFTs in macrophages and the necroptosis pathway can be targeted for disease intervention.
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What OpenQuestion holds
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.