ArticleThe Journal of experimental medicine2021
A mouse model of human TLR4 D299G/T399I SNPs reveals mechanisms of altered LPS and pathogen responses.
Article in The Journal of experimental medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 29 citations in OpenAlex.
- Mitochondrial reactive oxygen species regulate HIF-1α stabilization and methylglyoxal accumulation in classically activated mouse macrophages.Immunometabolism (Cobham, Surrey) · 2026Review
- IRAK2 deficiency causes immune dysregulation through defective Myddosome assembly and enhanced interferon responses.Nature communications · 2026Article
- Toll-like receptors in innate immunity and inflammation: from fundamental biology to clinic insights.Immunity & inflammation · 2026Review
- Endotoxin's Impact on Organism: From Immune Activation to Tolerance and Beyond.Journal of clinical medicine · 2025Review
- Intracellular methylglyoxal accumulation in classically activated mouse macrophages is mediated by HIF-1α.Journal of leukocyte biology · 2025Article
- Targeting Lung Damage: Amniotic Mesenchymal Stem Cells Mitigate Lipopolysaccharide-Induced Acute Lung Injury via Multiple Signaling Pathways.International journal of molecular sciences · 2025Article
- Article
- The immune receptors TLR4 and SLAMF1 regulate TNF release by human metapneumovirus in human macrophages.Frontiers in immunology · 2025Article
- BAP31 Promotes Adhesion Between Endothelial Cells and Macrophages Through the NF-κB Signaling Pathway in Sepsis.Journal of inflammation research · 2024Article
- Altered levels of IFN-γ, IL-4, and IL-5 depend on theFrontiers in immunology · 2024Article
- Gut Microbiota, Inflammatory Bowel Disease, and Cancer: The Role of Guardians of Innate Immunity.Cells · 2023Review
- TLR4 polymorphism and haplotype are associated with obesity and lipid profile in young population: a pilot study.Journal of endocrinological investigation · 2023Article
- Article
- Association of Toll-like receptor-4 polymorphism with SARS CoV-2 infection in Kurdish Population.Human gene (Amsterdam, Netherlands) · 2022Article
- E6020, a TLR4 Agonist Adjuvant, Enhances Both Antibody Titers and Isotype Switching in Response to Immunization with Hapten-Protein Antigens and Is Diminished in Mice with TLR4 Signaling Insufficiency.Journal of immunology (Baltimore, Md. : 1950) · 2022Article
- Mice Expressing Cosegregating Single Nucleotide Polymorphisms (D298G and N397I) in TLR4 Have Enhanced Responses to House Dust Mite Allergen.Journal of immunology (Baltimore, Md. : 1950) · 2022Article
- Protection against influenza-induced Acute Lung Injury (ALI) by enhanced induction of M2a macrophages: possible role of PPARγ/RXR ligands in IL-4-induced M2a macrophage differentiation.Frontiers in immunology · 2022Article
- TLR4 Gene Polymorphisms Interaction WithFrontiers in pediatrics · 2022Article
- Interaction of TLR4 and TLR8 in the Innate Immune Response against Mycobacterium Tuberculosis.International journal of molecular sciences · 2021Article
- Targeting TLR4 Signaling to Blunt Viral-Mediated Acute Lung Injury.Frontiers in immunology · 2021Review
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
Abstract
Two cosegregating single-nucleotide polymorphisms (SNPs) in human TLR4, an A896G transition at SNP rs4986790 (D299G) and a C1196T transition at SNP rs4986791 (T399I), have been associated with LPS hyporesponsiveness and differential susceptibility to many infectious or inflammatory diseases. However, many studies failed to confirm these associations, and transfection experiments resulted in conflicting conclusions about the impact of these SNPs on TLR4 signaling. Using advanced protein modeling from crystallographic data of human and murine TLR4, we identified homologous substitutions of these SNPs in murine Tlr4, engineered a knock-in strain expressing the D298G and N397I TLR4 SNPs homozygously, and characterized in vivo and in vitro responses to TLR4 ligands and infections in which TLR4 is implicated. Our data provide new insights into cellular and molecular mechanisms by which these SNPs decrease the TLR4 signaling efficiency and offer an experimental approach to confirm or refute human data possibly confounded by variables unrelated to the direct effects of the SNPs on TLR4 functionality.
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Registered trials
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