ArticleJournal of immunology (Baltimore, Md. : 1950)2011
Genome-wide expression profiling and mutagenesis studies reveal that lipopolysaccharide responsiveness appears to be absolutely dependent on TLR4 and MD-2 expression and is dependent upon intermolecular ionic interactions.
Article in Journal of immunology (Baltimore, Md. : 1950), 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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.
The trial behind it
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Who cites it
33 citing papers in PubMed, 46 citations in OpenAlex.
- Structural insight into TLR4/MD-2 activation by synthetic LPS mimetics with distinct binding modes.Nature communications · 2025Article
- Harnessing stem cell therapeutics in LPS-induced animal models: mechanisms, efficacies, and future directions.Stem cell research & therapy · 2025Review
- Dose-Dependent Effects of Lipopolysaccharide on the Endothelium-Sepsis versus Metabolic Endotoxemia-Induced Cellular Senescence.Antioxidants (Basel, Switzerland) · 2024Review
- Toll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen.Nature communications · 2023Article
- Exploring Species-Specificity in TLR4/MD-2 Inhibition with Amphiphilic Lipid A Mimicking Glycolipids.Molecules (Basel, Switzerland) · 2023Article
- Therapeutic Targeting of TLR4 for Inflammation, Infection, and Cancer: A Perspective for Disaccharide Lipid A Mimetics.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Understanding the development of Th2 cell-driven allergic airway disease in early life.Frontiers in allergy · 2022Review
- TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling.Cellular and molecular life sciences : CMLS · 2021Review
- Exploring electrostatic patterns of human, murine, equine and canine TLR4/MD-2 receptors.Innate immunity · 2020Article
- Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways.Frontiers in immunology · 2020Review
- Substrate structure-activity relationship reveals a limited lipopolysaccharide chemotype range for intestinal alkaline phosphatase.The Journal of biological chemistry · 2019Article
- Signaling Crosstalk Mechanisms That May Fine-Tune Pathogen-Responsive NFκB.Frontiers in immunology · 2019Review
- [Cathepsin B in hepatic Kupffer cells regulates activation of TLR4-independent inflammatory pathways in mice with lipopolysaccharide-induced sepsis].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2018Article
- Cathepsin B regulates non-canonical NLRP3 inflammasome pathway by modulating activation of caspase-11 in Kupffer cells.Cell proliferation · 2018Article
- Aminosugar-based immunomodulator lipid A: synthetic approaches.Beilstein journal of organic chemistry · 2018Review
- Innate Immune Receptors as Competitive Determinants of Cell Fate.Molecular cell · 2017Review
- CD14/TLR4 priming potentially recalibrates and exerts anti-tumor efficacy in tumor associated macrophages in a mouse model of pancreatic carcinoma.Scientific reports · 2016Article
- Bordetella pertussis Lipid A Recognition by Toll-like Receptor 4 and MD-2 Is Dependent on Distinct Charged and Uncharged Interfaces.The Journal of biological chemistry · 2015Article
- Novel perspectives on non-canonical inflammasome activation.ImmunoTargets and therapy · 2015Review
- Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4.CNS & neurological disorders drug targets · 2015Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
Lipid A (a hexaacylated 1,4' bisphosphate) is a potent immune stimulant for TLR4/MD-2. Upon lipid A ligation, the TLR4/MD-2 complex dimerizes and initiates signal transduction. Historically, studies also suggested the existence of TLR4/MD-2-independent LPS signaling. In this article, we define the role of TLR4 and MD-2 in LPS signaling by using genome-wide expression profiling in TLR4- and MD-2-deficient macrophages after stimulation with peptidoglycan-free LPS and synthetic Escherichia coli lipid A. Of the 1396 genes significantly induced or repressed by any one of the treatments in the wild-type macrophages, none was present in the TLR4- or MD-2-deficient macrophages, confirming that the TLR4/MD-2 complex is the only receptor for endotoxin and that both are required for responses to LPS. Using a molecular genetics approach, we investigated the mechanism of TLR4/MD-2 activation by combining the known crystal structure of TLR4/MD-2 with computer modeling. According to our murine TLR4/MD-2-activation model, the two phosphates on lipid A were predicted to interact extensively with the two positively charged patches on mouse TLR4. When either positive patch was abolished by mutagenesis into Ala, the responses to LPS and lipid A were nearly abrogated. However, the MyD88-dependent and -independent pathways were impaired to the same extent, indicating that the adjuvant activity of monophosphorylated lipid A most likely arises from its decreased potential to induce an active receptor complex and not more downstream signaling events. Hence, we concluded that ionic interactions between lipid A and TLR4 are essential for optimal LPS receptor activation.
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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.