ArticleThe Journal of experimental medicine2016
Complement pathway amplifies caspase-11-dependent cell death and endotoxin-induced sepsis severity.
Article in The Journal of experimental medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 87 papers.
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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
87 citing papers in PubMed, 150 citations in OpenAlex.
- The molecular mechanisms of pyroptosis and its implications in tumor immunotherapy.Molecular cancer · 2026Review
- Organelle stress in NLRP3 inflammasome: a central mediator of neurodegenerative diseases.Molecular neurodegeneration · 2026Review
- The mechanisms by which free heme exacerbates sepsis and the potential therapeutic targets.Frontiers in immunology · 2026Review
- Pyroptosis-induced tissue damage in kidney disease.Renal failure · 2025Review
- New insights into the noncanonical inflammasome point to caspase-4 as a druggable target.Nature reviews. Immunology · 2025Review
- Cardiolipin inhibits the non-canonical inflammasome by preventing LPS binding to caspase-4/11.The EMBO journal · 2025Article
- METTL3 mediates CPB1 expression by regulating transcription factor BACH2 to promote apoptosis and oxidative stress of lens epithelial cells.Journal of bioenergetics and biomembranes · 2025Article
- Immunomodulatory and cardio-protective effects of differentially originated multipotent mesenchymal stroma cells during polymicrobial sepsis in mice.European journal of trauma and emergency surgery : official publication of the European Trauma Society · 2025Article
- Peptidomics characteristics of pediatric sepsis.Scientific reports · 2025Article
- GSDMD-mediated pyroptosis: molecular mechanisms, diseases and therapeutic targets.Molecular biomedicine · 2025Review
- Carboxypeptidase B1 in dialyzed chronic kidney disease patients.Scientific reports · 2025Article
- Review
- Comprehensive characterization of multi-omics landscapes between gut microbial metabolites and the druggable genome in sepsis.Frontiers in immunology · 2025Article
- Mechanisms and cross-talk of regulated cell death and their epigenetic modifications in tumor progression.Molecular cancer · 2024Review
- The dysfunction of complement and coagulation in diseases: the implications for the therapeutic interventions.MedComm · 2024Review
- Article
- Sepsis-Induced Endothelial Dysfunction: Permeability and Regulated Cell Death.Journal of inflammation research · 2024Review
- Salmonella spvC gene suppresses macrophage/neutrophil antibacterial defense mediated by gasdermin D.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2024Article
- Evidence from Machine Learning, Diagnostic Hub Genes in Sepsis and Diagnostic Models based on Xgboost Models, Novel Molecular Models for the Diagnosis of Sepsis.Current medicinal chemistry · 2024Article
- Review
27 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
10 authors at 2 institutions in 1 country.
Funding
Abstract
Cell death and release of proinflammatory mediators contribute to mortality during sepsis. Specifically, caspase-11-dependent cell death contributes to pathology and decreases in survival time in sepsis models. Priming of the host cell, through TLR4 and interferon receptors, induces caspase-11 expression, and cytosolic LPS directly stimulates caspase-11 activation, promoting the release of proinflammatory cytokines through pyroptosis and caspase-1 activation. Using a CRISPR-Cas9-mediated genome-wide screen, we identified novel mediators of caspase-11-dependent cell death. We found a complement-related peptidase, carboxypeptidase B1 (Cpb1), to be required for caspase-11 gene expression and subsequent caspase-11-dependent cell death. Cpb1 modifies a cleavage product of C3, which binds to and activates C3aR, and then modulates innate immune signaling. We find the Cpb1-C3-C3aR pathway induces caspase-11 expression through amplification of MAPK activity downstream of TLR4 and Ifnar activation, and mediates severity of LPS-induced sepsis (endotoxemia) and disease outcome in mice. We show C3aR is required for up-regulation of caspase-11 orthologues, caspase-4 and -5, in primary human macrophages during inflammation and that c3aR1 and caspase-5 transcripts are highly expressed in patients with severe sepsis; thus, suggesting that these pathways are important in human sepsis. Our results highlight a novel role for complement and the Cpb1-C3-C3aR pathway in proinflammatory signaling, caspase-11 cell death, and sepsis severity.
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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.