Affinage

TLR4

Toll-like receptor 4 · UniProt O00206

Length
839 aa
Mass
95.7 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TLR4 is the central transmembrane pattern-recognition receptor of the mammalian innate immune system, identified by positional cloning as the sensor responsible for LPS-induced signaling (PMID:12467247). Ligand detection occurs through the TLR4–MD-2 co-receptor complex, which recognizes LPS in a cascade involving LBP and CD14 and assembles into an activated 2:2:2 (TLR4:MD-2:LPS) homodimer, with defined residues governing agonist/antagonist binding (PMID:24310172, PMID:24339336). Once engaged, TLR4 signals through bifurcated, location-dependent adaptor circuitry: at the plasma membrane the bridging factor Mal recruits MyD88 to activate IRAK and TRAF6, driving NF-κB activation, whereas upon endosomal internalization TLR4 switches to a TRAM-bridged, MyD88-independent TRIF pathway to induce type I interferons (PMID:9734363, PMID:22196451). This adaptor logic is targetable: the small molecule TAK-242 binds Cys747 in the TLR4 intracellular domain and disrupts both the TLR4–TIRAP and TLR4–TRAM interactions, blocking MyD88- and TRIF-dependent outputs (PMID:20881006), and signaling is intrinsically restrained by a MyD88–PI3K(p85) complex docking on the YXXM motif of MyD88 (PMID:19289601) and by a FoxO1–AKT feedback loop that controls Tlr4 transcription (PMID:21045807). Beyond endotoxin, TLR4 senses endogenous danger ligands including HMGB1 (in a redox-state-dependent manner) and fibrinogen, and cooperates with accessory partners such as uPAR/CD36 and annexin A2 to amplify inflammatory responses (PMID:16878026, PMID:23148306, PMID:33362762, PMID:27856281, PMID:21091668). Downstream of these inputs TLR4 engages cell-type-specific effectors—JNK/p38 MAPK in hepatic and monocytic inflammation (PMID:27856281, PMID:31539158), necrosome assembly via both MyD88 and TRIF (PMID:32094226), a SIRT2/p53/caspase apoptotic axis in cardiomyocytes (PMID:33159115), and ER stress/CHOP signaling that suppresses adaptive thermogenesis (PMID:26370079)—thereby mediating inflammation, programmed cell death, and metabolic adaptation across diverse tissues.

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1998 High

    Established the core adaptor logic of TLR4 by placing MyD88, IRAK, and TRAF6 downstream of the receptor, defining how an innate receptor converts ligand sensing into NF-κB activation.

    Evidence Dominant-negative and overexpression epistasis with NF-κB reporters in transfected cells

    PMID:9734363

    Open questions at the time
    • Did not identify the physiological ligand
    • AP-1 activation mechanism left distinct from IL-1R but undefined
  2. 2002 High

    Identified TLR4 itself as the LPS receptor, answering what molecule senses endotoxin and anchoring TLR4 as the endotoxin sensor of innate immunity.

    Evidence Positional cloning of LPS-hyporesponsive mouse mutants plus knockout corroboration

    PMID:12467247

    Open questions at the time
    • Did not resolve the structural basis of LPS recognition
    • Role of co-receptors not defined here
  3. 2005 Medium

    Revealed a homeostatic, non-inflammatory role for basal TLR4 signaling by commensal LPS in distributing activated T cells, broadening TLR4 function beyond acute pathogen response.

    Evidence TLR4-deficient mice under basal conditions with flow-cytometric quantification of hepatic CD8+ T-cell trapping

    PMID:16034104

    Open questions at the time
    • Adaptor/effector pathway for T-cell trapping unidentified
    • Single phenotype, single lab
  4. 2006 Medium

    Extended TLR4 ligand recognition to the endogenous danger signal HMGB1, establishing TLR4/MyD88 as a sensor of sterile injury, not only microbial LPS.

    Evidence Knockout macrophages, neutralizing antibodies, and transfected HEK293 cells with cytokine readouts

    PMID:16878026

    Open questions at the time
    • Differential results between cell types complicate interpretation
    • Direct HMGB1–TLR4 binding not demonstrated here
  5. 2007 Medium

    Showed TLR4 can drive lipid-mediator (5-LO eicosanoid) output independently of NF-κB-driven protein synthesis when combined with Ca2+ influx, revealing a transcription-independent arm of TLR4 signaling.

    Evidence LC/MS-MS eicosanoid profiling with NF-κB inhibition and Ca2+ manipulation in RAW264.7 macrophages

    PMID:17535806

    Open questions at the time
    • Molecular link from TLR4 to 5-LO activation unmapped
    • Requires synergistic Ca2+ signal of undefined source
  6. 2009 Medium

    Defined a built-in negative-regulatory mechanism whereby a MyD88–PI3K(p85) complex docks via the MyD88 YXXM motif to restrain TLR4 output, addressing how signaling is self-limited.

    Evidence Reciprocal Co-IP with MyD88 structure-function mutants plus Akt phosphorylation in MyD88-/- macrophages

    PMID:19289601

    Open questions at the time
    • Quantitative contribution to signal damping in vivo unclear
    • Single lab
  7. 2010 High

    Resolved how a single inhibitor blocks both TLR4 outputs: TAK-242 binds Cys747 and disrupts TLR4–TIRAP and TLR4–TRAM interactions, pinpointing an intracellular druggable site.

    Evidence Reciprocal Co-IP in HEK293, NF-κB/ISRE reporters, and IRAK activation in RAW264.7

    PMID:20881006

    Open questions at the time
    • Structural detail of the Cys747 binding pocket not solved here
    • Selectivity across TLR family not fully mapped
  8. 2010 Medium

    Identified a transcriptional feed-forward/feedback loop in which FoxO1 promotes Tlr4 expression while TLR4-induced AKT inactivates FoxO1, explaining self-limiting macrophage inflammation.

    Evidence ChIP-Seq of FoxO1 binding plus FoxO1 KO/KD macrophage cytokine assays

    PMID:21045807

    Open questions at the time
    • Direct demonstration of loop dynamics in vivo limited
    • Single lab
  9. 2011 Medium

    Articulated the spatial bifurcation of TLR4 signaling—Mal/MyD88 at the membrane versus TRAM/TRIF in endosomes—explaining how one receptor produces both cytokines and type I interferons.

    Evidence Synthesis of structural and cell-biology data including adaptor localization and pH-sensitivity

    PMID:22196451

    Open questions at the time
    • Integrative model rather than single primary dataset
    • Trafficking machinery driving the switch not detailed here
  10. 2013 High

    Provided the structural mechanism of LPS recognition, showing the TLR4/MD-2/LPS 2:2:2 activated homodimer and the residues governing agonist/antagonist binding.

    Evidence Crystal structure analysis of TLR4/MD-2/LPS complexes

    PMID:24310172

    Open questions at the time
    • Dynamics of dimerization in membranes not captured
    • Co-receptor CD14/LBP handoff geometry not resolved
  11. 2013 Medium

    Demonstrated druggable dual targeting of the recognition module by a lipid A mimetic that binds MD-2 and engages CD14, defining co-receptor-level antagonism.

    Evidence NMR of compound–MD-2 binding, docking, CD14 internalization, and TLR4 signaling inhibition in HEK-blue and macrophages

    PMID:24339336

    Open questions at the time
    • In vivo efficacy not established
    • Single lab
  12. 2012 High

    Linked redox-defined HMGB1 to TLR4 in a non-immune tissue, showing TLR4 (not RAGE) drives muscle fatigue via impaired SR Ca2+ release, expanding TLR4 effector outputs beyond cytokines.

    Evidence Single intact muscle fibers from TLR4-/- vs. RAGE-/- mice with Ca2+ measurements and defined HMGB1 redox states

    PMID:23148306

    Open questions at the time
    • Intracellular pathway from TLR4 to SR Ca2+ handling unmapped
    • Adaptor usage in muscle not defined
  13. 2020 High

    Defined how TLR4 controls regulated necroptosis, showing necrosome activation through both MyD88 and TRIF and its restraint by MK2 and the RNA-binding protein TTP/ZFP36.

    Evidence LPS stimulation across WT, MyD88-/-, Trif-/-, double-KO, MK2-/-, and Zfp36-/- macrophages with necrosome, cytokine, and cell-death readouts

    PMID:32094226

    Open questions at the time
    • Precise molecular target of TTP within the necrosome pathway not pinpointed
    • Relevance in vivo not tested here
  14. 2020 Medium

    Connected TLR4 to metabolic suppression of thermogenesis, placing TLR4 upstream of ER stress/CHOP in blocking cAMP-induced UCP1 in adipocytes.

    Evidence LPS/HFD in vivo, TLR4 siRNA, CHOP KO mice, and chemical chaperone with UCP1 readouts

    PMID:26370079

    Open questions at the time
    • Adaptor route from TLR4 to ER stress not defined
    • Single lab
  15. 2020 Medium

    Identified a TLR4-driven apoptotic axis in cardiomyocytes operating through SIRT2 loss, p53 acetylation, and caspase activation, defining a cell-death effector branch.

    Evidence LPS in rats and H9c2 cells with TLR4/SIRT2 overexpression and pathway protein blotting

    PMID:33159115

    Open questions at the time
    • Link between TLR4 proximal signaling and SIRT2 regulation unmapped
    • Single lab
  16. 2020 Medium

    Placed uPAR (with CD36) in the TLR4 membrane interactome as a positive regulator of LPS-induced NF-κB signaling and sepsis inflammation.

    Evidence Co-localization/Co-IP of uPAR with TLR4 and CD36, uPAR knockdown, and uPAR-/- mice in CLP sepsis

    PMID:33362762

    Open questions at the time
    • Direct binding interface not defined
    • Mechanism of signal enhancement unclear
  17. 2010 Medium

    Showed TLR4 cooperates with annexin A2 to sense the anti-β2GPI/β2GPI complex and drive tissue factor expression, expanding the receptor's prothrombotic ligand repertoire.

    Evidence β2GPI affinity pulldown of TLR4 and ANX2 with ANX2-RNAi and TLR4/MD-2/MyD88/TF blotting in THP-1 cells

    PMID:21091668

    Open questions at the time
    • Stoichiometry of TLR4–ANX2 cooperation unknown
    • Single lab
  18. 2010 Medium

    Mapped TLR4-induced organelle-resolved lipidome remodeling, revealing that activation reshapes sterol, ceramide, cardiolipin, and ether-lipid pools across compartments.

    Evidence Subcellular fractionation and LC-MS/MS lipidomics of 229 species in RAW264.7 macrophages

    PMID:20574076

    Open questions at the time
    • Causal signaling link from TLR4 to specific lipid changes not established
    • Functional consequence per organelle unclear
  19. 1999 Medium

    Showed in cardiac myocytes that constitutively active TLR4 activates NF-κB but not AP-1 or iNOS, demonstrating cell-type-specific selectivity of TLR4 transcriptional outputs.

    Evidence Constitutively active TLR4 chimera with NF-κB/AP-1/iNOS reporters and PDTC inhibition in cardiac myocytes

    PMID:10430608

    Open questions at the time
    • Basis for restricted AP-1/iNOS activation undefined
    • Reliant on chimeric construct
  20. 2016 Medium

    Demonstrated a protective TLR4/MyD88 function in B1a B cells required for natural IgM secretion and atheroprotection, illustrating context-dependent beneficial roles.

    Evidence Adoptive transfer of WT vs. TLR4-/-/MyD88-/- B1a cells into ApoE-/- mice with lesion and IgM endpoints

    PMID:27930350

    Open questions at the time
    • Ligand driving B1a TLR4 function unidentified
    • Single lab
  21. 2018 Medium

    Identified adsorbed fibrinogen as a TLR4 ligand on monocytes driving ERK/JNK MAPK activation and BMP-2 production, linking TLR4 to a pro-osteogenic response.

    Evidence Flow cytometry, MAPK phospho-blotting, TLR4 pharmacological inhibition, and BMP-2 measurement in human monocytes

    PMID:27856281

    Open questions at the time
    • Direct fibrinogen–TLR4 binding not biochemically resolved
    • Single lab
  22. 2019 Medium

    Defined a TLR4/PKCε pathway in nociceptors mediating opioid-induced hyperalgesia and priming, distinguishing low-dose from high-dose morphine mechanisms.

    Evidence Intrathecal TLR4 and PKCε antisense oligonucleotides with nociceptive threshold readouts in rats

    PMID:31209174

    Open questions at the time
    • Endogenous TLR4 ligand in OIH unidentified
    • Adaptor usage in nociceptors not defined
  23. 2019 Medium

    Showed TLR4 drives acetaminophen-induced liver inflammation via JNK activation, defining a MAPK effector branch in sterile hepatic injury.

    Evidence TLR4-/- vs. WT mice with histology, cytokine, and phospho-JNK/p38 readouts plus TLR4 siRNA in RAW264.7

    PMID:31539158

    Open questions at the time
    • Proximal ligand/adaptor coupling to JNK not delineated
    • Single lab
  24. 2019 Medium

    Demonstrated TLR4 mediates acute heme-induced renal vasoconstriction and NF-κB/MCP-1 induction while sparing the Nrf2/HO-1 axis, dissecting which heme responses depend on TLR4.

    Evidence TAK-242 in vivo, TLR4-/- mice, renal blood flow, and NF-κB/Nrf2 reporters in renal epithelial cells

    PMID:28978536

    Open questions at the time
    • Mechanism of heme engagement of TLR4 unresolved
    • Does not mediate glycerol-induced AKI
  25. 2010 Medium

    Showed TLR4 induces B1 bradykinin receptor expression in cardiac fibroblasts, revealing TLR4–B1R crosstalk modulating PGI2, NO, and collagen in cardiac inflammation.

    Evidence qRT-PCR/Western blot for B1R/COX-2/iNOS with LPS priming and DAKD stimulation across human, rat, and mouse fibroblasts

    PMID:29775649

    Open questions at the time
    • Signaling route from TLR4 to B1R transcription unmapped
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the spatial adaptor switch is physically controlled by trafficking machinery, and how diverse endogenous ligands (HMGB1, fibrinogen, heme, β2GPI complexes) are differentially read to select cell-type-specific effector branches (JNK, SIRT2/p53, ER stress/CHOP, PKCε), remains unresolved.
  • No unified mechanism linking ligand identity to downstream effector selection
  • Trafficking determinants of the MyD88-to-TRIF switch not biochemically defined
  • Many tissue-specific effector branches rest on single-lab studies

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0001618 virus receptor activity 2 GO:0008289 lipid binding 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005886 plasma membrane 2 GO:0005768 endosome 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-8953897 Cellular responses to stimuli 1
Partners
CD14CD36MD2 (LY96)MYD88PIK3R1TIRAPTRAM (TICAM2)UPAR (PLAUR)
Complex memberships
TLR4:MD-2:LPS activated homodimer

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 TLR4 (hToll) signals through the adaptor protein MyD88, which in turn activates the kinase IRAK and the TRAF6 protein to activate NF-κB; AP-1 activation differs from IL-1R signaling, establishing MyD88 as a general adaptor for the Toll/IL-1R family. Dominant-negative and overexpression constructs in cell transfection assays; epistasis between hToll, MyD88, IRAK, and TRAF6 measured by NF-κB reporter assays Molecular cell High 9734363
2002 TLR4 was identified by positional cloning as the central component of the mammalian LPS receptor, establishing it as the endotoxin sensor responsible for LPS-induced innate immune signaling. Positional cloning in LPS-hyporesponsive mouse mutants; gene knockout studies Current topics in microbiology and immunology High 12467247
2010 TAK-242 (resatorvid) binds selectively to TLR4 at Cys747 in the intracellular domain and disrupts protein-protein interactions between TLR4 and its adaptor molecules TIRAP and TRAM, thereby inhibiting both MyD88-dependent (NF-κB) and TRIF-dependent (ISRE) signaling pathways. Co-immunoprecipitation in HEK293 cells overexpressing TLR4/MD-2 with TIRAP or TRAM; NF-κB and ISRE reporter assays; IRAK activation assay in RAW264.7 cells Molecular pharmacology High 20881006
2006 HMGB1 signals through TLR4 (and TLR2) to induce cytokine production; in primary macrophages from TLR4 and MyD88 knockout mice, HMGB1-induced TNF release is significantly reduced compared to wild-type controls, placing TLR4/MyD88 in the HMGB1 signaling pathway. Neutralizing anti-TLR4/TLR2 antibodies in human whole blood and primary macrophages; TNF/IL-8 cytokine measurements; knockout macrophages (TLR4-/-, MyD88-/-, TLR2-/-); TLR2/TLR4-transfected HEK293 cells Shock (Augusta, Ga.) Medium 16878026
2009 MyD88 associates with PI3K p85 via a YXXM motif in the MyD88 TIR domain; sustained interaction of the MyD88/PI3K complex with the TLR4 intracellular signaling platform negatively regulates TLR4 signaling. LPS-induced Akt phosphorylation is TLR4-dependent and MyD88-dependent. Co-immunoprecipitation of MyD88 variants (YXXM→YXXA, TIR-domain deletion, death-domain deletion) with p85, TLR4, and WT MyD88; Akt phosphorylation assays in wild-type vs. MyD88-/- macrophages Journal of leukocyte biology Medium 19289601
2010 FoxO1 transcription factor binds to multiple enhancer-like elements within the Tlr4 gene itself and in Tlr4 pathway genes, promoting Tlr4 expression and macrophage inflammatory signaling; TLR4 activation in turn induces AKT which inactivates FoxO1, establishing a self-limiting inflammatory loop. ChIP-Seq to identify FoxO1 binding sites; FoxO1 knockout/knockdown macrophage studies; reporter and cytokine secretion assays The EMBO journal Medium 21045807
2011 TLR4 initiates distinct signaling pathways depending on cellular location: at the plasma membrane, bridging factor Mal recruits MyD88 leading to proinflammatory cytokine production; upon internalization into endosomes, TLR4 uses TRAM as a bridging factor to activate the MyD88-independent/TRIF pathway leading to type I interferon expression. Analysis of crystal structure data (TLR3-dsRNA complex used as model), combined with published biochemical and cell biology evidence reviewed and synthesized; pH-sensitivity experiments and adaptor localization data Trends in biochemical sciences Medium 22196451
2012 HMGB1 acts via TLR4 (but not RAGE) to accelerate muscle fatigue by impairing sarcoplasmic reticulum Ca2+ release in skeletal muscle fibers; signaling requires HMGB1 with a reduced Cys106 and a disulfide bond between Cys23 and Cys45. Single intact muscle fiber preparations from wild-type, TLR4-/-, and RAGE-/- mice; Ca2+ measurements during tetanic contractions; recombinant HMGB1 with defined redox states; immunofluorescence and confocal microscopy for TLR4 and MHC-I co-expression Annals of the rheumatic diseases High 23148306
2013 The TLR4-MD-2 complex recognizes LPS in a cascade involving LBP and CD14; structural studies show how the TLR4/MD-2 complex forms a 2:2:2 (TLR4:MD-2:LPS) activated homodimer, with Arg241 of TLR4 and Tyr102, Ser120, Lys122 of MD-2 important for antagonist binding. Crystal structure analysis of TLR4/MD-2/LPS complexes; structural basis reviewed from published crystal structures Experimental & molecular medicine High 24310172
2013 A synthetic monosaccharide lipid A mimetic (compound 3) directly binds the MD-2 co-receptor (confirmed by NMR and molecular modeling) and also interacts with CD14, stimulating its internalization; dual targeting of MD-2 and CD14 inhibits TLR4 signaling, with greater effect at low LPS concentration when CD14 is important. NMR spectroscopy of compound-MD-2 interaction; molecular modeling/docking; CD14 internalization assay; TLR4 signaling inhibition in HEK-blue cells and murine macrophages Chembiochem : a European journal of chemical biology Medium 24339336
1999 Constitutively active TLR4 (CD4/hTLR4 chimera) activates an NF-κB reporter in cardiac myocytes but does not activate AP-1 or iNOS reporter constructs; TLR4 expression in cardiac myocytes is enhanced by LPS or IL-1β, an effect inhibited by the antioxidant PDTC. Transfection of constitutively active TLR4 construct with NF-κB, AP-1, and iNOS reporter constructs in cardiac myocytes; LPS/IL-1β stimulation; PDTC inhibition The Journal of clinical investigation Medium 10430608
2020 TLR4 activation promotes cardiomyocyte apoptosis through a pathway involving decreased SIRT2 expression, increased p53 acetylation, and activation of caspase-7 and caspase-9; TLR4 overexpression in H9c2 cells recapitulates nuclear p53 translocation and mitochondrial dysfunction. LPS treatment of rats (osmotic pump) and H9c2 cells; TLR4 and SIRT2 cDNA overexpression; Western blotting for p53 acetylation, cleaved caspase-7/caspase-9; mitochondrial complex activity assays Scientific reports Medium 33159115
2020 During TLR4 signaling, necrosome activation in macrophages is mediated through both MyD88 and TRIF adaptor proteins and is inhibited by MK2; the RNA-binding protein tristetraprolin (TTP/ZFP36) inhibits TNFα/JNK-induced necrosome signaling during tonic TLR4 stimulation, preventing necroptosis. LPS stimulation of macrophages from WT, MyD88-/-, Trif-/-, MyD88-/-Trif-/-, MK2-/-, and Zfp36-/- mice; immunoblotting for necrosome components; ELISA for cytokines; cell death assays The Journal of biological chemistry High 32094226
2020 TLR4 activation by LPS abolishes cAMP-induced UCP1 upregulation in primary human adipocytes via endoplasmic reticulum stress; silencing of CHOP (a downstream ER stress mediator) or chemical chaperone treatment reverses LPS-induced suppression of adaptive thermogenesis, placing TLR4 upstream of ER stress/CHOP in suppressing UCP1 expression. LPS and high-fat diet treatment in vivo; siRNA-mediated TLR4 silencing; CHOP knockout mice; chemical chaperone treatment; UCP1 expression assays in primary human adipocytes The Journal of biological chemistry Medium 26370079
2020 uPAR (urokinase receptor) is a component of the TLR4 interactome; uPAR co-localizes and interacts with TLR4 on the cell membrane along with scavenger receptor CD36; downregulation of uPAR diminishes LPS-induced TLR4 signaling and NF-κB activation in myeloid and non-myeloid cells, and uPAR-/- mice show reduced inflammatory response in polymicrobial sepsis. Co-localization and co-immunoprecipitation of uPAR with TLR4 and CD36; uPAR knockdown in vitro; uPAR-/- mice in cecal ligation and puncture sepsis model; NFκB activation and cytokine assays Frontiers in immunology Medium 33362762
2019 In nociceptors, TLR4 mediates opioid-induced hyperalgesia (OIH) and hyperalgesic priming induced by low-dose morphine; antisense knockdown of TLR4 in nociceptors prevented OIH and priming; this mechanism requires PKCε signaling downstream of TLR4. High-dose morphine-induced analgesia and priming are TLR4-independent. Intrathecal antisense oligodeoxynucleotide (AS-ODN) to TLR4 mRNA; PKCε AS-ODN; saporin-based nociceptor depletion; nociceptive threshold measurements in rats The Journal of neuroscience Medium 31209174
2010 TLR4 activation by LPS in macrophages causes significant subcellular lipidome remodeling across multiple organelles: ceramide and cholesterol precursors (desmosterol, lanosterol) increase in all compartments; oxidized sterols increase and unsaturated cardiolipins decrease in mitochondria; unsaturated ether-linked phosphatidylethanolamines decrease in the ER. Subcellular fractionation (nuclei, mitochondria, ER, plasmalemma, cytoplasm) of RAW264.7 macrophages; liquid chromatography/tandem mass spectrometry lipidomics of 229 lipid species Journal of lipid research Medium 20574076
2016 TLR4 and MyD88 expressed on peritoneal B1a B cells are required for their natural IgM secretion and atheroprotective function; adoptive transfer of TLR4-/- or MyD88-/- B1a cells failed to suppress atherosclerosis, reduce lesion apoptotic cells, or modulate T-cell infiltrates in ApoE-/- mice. Adoptive transfer of WT, TLR4-/-, TLR2-/-, TLR9-/-, or MyD88-/- B1a cells into splenectomized ApoE-/- mice fed high-fat diet; atherosclerosis quantification; IgM ELISA; immunohistochemistry of lesions Journal of the American Heart Association Medium 27930350
2018 Adsorbed fibrinogen interacts with TLR4 on human monocytes, triggering ERK1/2 and JNK MAPK activation (but not p38) and inducing BMP-2 production; pharmacological TLR4 inhibition reduces both ERK/JNK phosphorylation and BMP-2 expression, establishing TLR4 as the upstream receptor for this pro-osteogenic pathway. Flow cytometry for TLR4 cell surface expression; Western blot for MAPK phosphorylation; specific TLR4 pharmacological inhibitor; BMP-2 mRNA and protein measurement in primary human monocytes on fibrinogen-coated chitosan substrates Acta biomaterialia Medium 27856281
2021 LPS/TLR4 signaling regulates osteoclastogenesis independent of the RANKL/RANK/OPG axis; TLR4 inhibitor TAK-242 blocks LPS-induced osteoclast differentiation and TNF-α secretion, and the pathway operates through LPS/TLR4/TNF-α/TNFR-2 autocrine/paracrine signaling. RAW264.7 differentiation assays; TAK-242 TLR4 inhibition; anti-TNF-α antibody blocking; membrane TLR4 and TNFR-2 level measurement; RANKL-primed then LPS-treated experimental design BMC immunology Medium 33765924
2019 TLR4 mediates acute heme-induced renal vasoconstriction; heme activates NF-κB and MCP-1 expression in renal epithelial cells via TLR4 signaling (blocked by TAK-242), but TLR4 does not mediate the anti-inflammatory Nrf2/HO-1 response to heme and does not mediate major mechanisms of glycerol-induced heme protein AKI. TAK-242 TLR4 antagonist in vivo; TLR4+/+ vs. TLR4-/- mice; renal blood flow measurement; NF-κB and Nrf2 reporter assays in renal epithelial cells; glycerol AKI model American journal of physiology. Renal physiology Medium 28978536
2005 TLR4 is required for in vivo trapping of activated CD8+ T cells in the liver; in TLR4-deficient mice, the liver is compromised in its ability to sequester activated CD8+ T cells, revealing a role for basal TLR4 signaling by commensal LPS in regulating T cell distribution. TLR4-deficient mice (basal conditions, no exogenous inflammation); flow cytometry quantification of activated CD8+ T cells in liver vs. circulation; correlation analysis Journal of immunology Medium 16034104
2010 TLR4 activation induces B1 bradykinin receptor (B1R) expression in cardiac fibroblasts via upregulation of B1R mRNA and protein; LPS-primed cardiac fibroblasts show enhanced DAKD (B1R agonist)-induced PGI2 secretion and NO production and reduced collagen I levels, revealing TLR4-B1R crosstalk in cardiac inflammation. qRT-PCR and Western blot for B1R, COX-2, iNOS in primary human, rat, and mouse cardiac fibroblasts; LPS pretreatment; DAKD stimulation; PGI2 and NO measurement Toxicology and applied pharmacology Medium 29775649
2007 TLR4 ligand (LPS/Kdo2-lipid A) synergizes with sustained Ca2+ influx to activate the 5-lipoxygenase (5-LO) eicosanoid pathway in macrophages, independent of NF-κB-mediated protein synthesis; COX metabolite profiles are unaffected by TLR stimulation alone. LC/MS-MS quantification of >60 eicosanoids in RAW264.7 macrophages stimulated with 16 agonists; NF-κB inhibition to dissect protein synthesis-dependent vs. -independent pathways; Ca2+ influx manipulation The Journal of biological chemistry Medium 17535806
2010 TLR4 mediates anti-β2GPI/β2GPI-induced tissue factor (TF) expression in THP-1 monocytic cells; both TLR4 and annexin A2 (ANX2) can bind β2GPI, and ANX2-RNAi knockdown diminishes TLR4, MD-2, MyD88, and TF expression in response to the complex, revealing cooperative ANX2-TLR4 signaling. β2GPI affinity column pulldown showing TLR4 and ANX2 binding; ANX2-specific RNAi lentivirus knockdown; Western blot for TLR4/MD-2/MyD88/TF; paclitaxel competition with MD-2 ligand Clinical and experimental immunology Medium 21091668
2019 TLR4-dependent activation of the JNK signaling pathway promotes APAP-induced liver inflammation; TLR4-/- mice show attenuated JNK phosphorylation, reduced inflammatory cytokines, and less macrophage/neutrophil infiltration after acetaminophen challenge; TLR4 siRNA in RAW264.7 cells similarly inhibits JNK and p38 phosphorylation. TLR4-/- vs. WT mice treated with APAP; liver histology, ALT/GSH measurement; RT-qPCR and ELISA for cytokines; Western blot for phospho-JNK and phospho-p38; flow cytometry for immune cell infiltration; TLR4-siRNA in RAW264.7 European review for medical and pharmacological sciences Medium 31539158

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Molecular cell 1233 9734363
2013 Recognition of lipopolysaccharide pattern by TLR4 complexes. Experimental & molecular medicine 979 24310172
2006 HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. Shock (Augusta, Ga.) 707 16878026
1999 Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. The Journal of clinical investigation 542 10430608
2010 TAK-242 (resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules. Molecular pharmacology 510 20881006
2006 TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer research 427 16585214
2008 TLR-4, IL-1R and TNF-R signaling to NF-kappaB: variations on a common theme. Cellular and molecular life sciences : CMLS 373 18535784
2023 Toll-like receptor 4 (TLR4): new insight immune and aging. Immunity & ageing : I & A 307 38001481
2021 COVID-19 and Toll-Like Receptor 4 (TLR4): SARS-CoV-2 May Bind and Activate TLR4 to Increase ACE2 Expression, Facilitating Entry and Causing Hyperinflammation. Mediators of inflammation 285 33505220
2009 TLR4/MyD88/PI3K interactions regulate TLR4 signaling. Journal of leukocyte biology 277 19289601
2022 Toll-like receptor 4 (TLR4) inhibitors: Current research and prospective. European journal of medicinal chemistry 250 35307617
2007 Toll-like receptor (TLR)-2 and TLR-4 regulate inflammation, gliosis, and myelin sparing after spinal cord injury. Journal of neurochemistry 236 17403033
2010 FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages. The EMBO journal 214 21045807
2015 Hepatic TLR4 signaling in obese NAFLD. American journal of physiology. Gastrointestinal and liver physiology 209 26113297
2005 Toll-like receptor (TLR) polymorphisms in African children: Common TLR-4 variants predispose to severe malaria. Proceedings of the National Academy of Sciences of the United States of America 205 16371473
2002 TLR4 as the mammalian endotoxin sensor. Current topics in microbiology and immunology 196 12467247
2010 TLR4 and Insulin Resistance. Gastroenterology research and practice 180 20814545
2010 Subcellular organelle lipidomics in TLR-4-activated macrophages. Journal of lipid research 165 20574076
2013 Toll-like receptor 4 (TLR4) modulation by synthetic and natural compounds: an update. Journal of medicinal chemistry 147 24188011
2011 Therapeutic targeting of innate immunity with Toll-like receptor 4 (TLR4) antagonists. Biotechnology advances 138 21664961
2008 TLR-4 deficiency protects against focal cerebral ischemia and axotomy-induced neurodegeneration. Neurobiology of disease 132 18486483
2012 Synthetic Toll like receptor-4 (TLR-4) agonist peptides as a novel class of adjuvants. PloS one 130 22363498
2015 TLR-4 may mediate signaling pathways of Astragalus polysaccharide RAP induced cytokine expression of RAW264.7 cells. Journal of ethnopharmacology 121 26743224
2014 Toll like receptor 4 (TLR4) mediates the stimulating activities of chitosan oligosaccharide on macrophages. International immunopharmacology 108 25237008
2017 The interplay between Angiotensin II, TLR4 and hypertension. Pharmacological research 103 28330785
2013 Should a Toll-like receptor 4 (TLR-4) agonist or antagonist be designed to treat cancer? TLR-4: its expression and effects in the ten most common cancers. OncoTargets and therapy 99 24235843
2015 Activation of Toll-like receptor 4 (TLR4) attenuates adaptive thermogenesis via endoplasmic reticulum stress. The Journal of biological chemistry 95 26370079
2012 TLR-4 signalling accelerates colon cancer cell adhesion via NF-κB mediated transcriptional up-regulation of Nox-1. PloS one 92 23071493
2007 TLR-4 and sustained calcium agonists synergistically produce eicosanoids independent of protein synthesis in RAW264.7 cells. The Journal of biological chemistry 84 17535806
2012 TLR4 as receptor for HMGB1 induced muscle dysfunction in myositis. Annals of the rheumatic diseases 80 23148306
2021 Lipopolysaccharide- TLR-4 Axis regulates Osteoclastogenesis independent of RANKL/RANK signaling. BMC immunology 78 33765924
2009 TLR-2, TLR-4 and dectin-1 expression in human monocytes and neutrophils stimulated by Paracoccidioides brasiliensis. Medical mycology 72 19888805
2021 Toll-like receptor 4 (TLR4) antagonists as potential therapeutics for intestinal inflammation. Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology 71 33666891
2020 Activation of toll like receptor 4 (TLR4) promotes cardiomyocyte apoptosis through SIRT2 dependent p53 deacetylation. Scientific reports 71 33159115
2007 Expression of TLR-2, TLR-4, NOD2 and pNF-kappaB in a neonatal rat model of necrotizing enterocolitis. PloS one 71 17971865
2015 Structure-Activity Relationships of (+)-Naltrexone-Inspired Toll-like Receptor 4 (TLR4) Antagonists. Journal of medicinal chemistry 70 26010811
2012 Hyaluronan differently modulates TLR-4 and the inflammatory response in mouse chondrocytes. BioFactors (Oxford, England) 70 22287316
2007 Enhanced IL-10 production by TLR4- and TLR2-primed dendritic cells upon TLR restimulation. Journal of immunology (Baltimore, Md. : 1950) 70 17475844
2012 Toll-like receptors (TLR2 and TLR4) recognize polysaccharides of Pseudallescheria boydii cell wall. Carbohydrate research 63 22507831
2011 Different dimerisation mode for TLR4 upon endosomal acidification? Trends in biochemical sciences 60 22196451
2009 Polymorphisms in Toll-like receptor 4 (TLR4) are associated with protection against leprosy. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology 60 19430824
2018 Cilostazol disrupts TLR-4, Akt/GSK-3β/CREB, and IL-6/JAK-2/STAT-3/SOCS-3 crosstalk in a rat model of Huntington's disease. PloS one 59 30260985
2005 TLR-4 pathway mediates the inflammatory response but not bacterial elimination in E. coli pneumonia. American journal of physiology. Lung cellular and molecular physiology 57 16024722
2020 The Emerging Role of Curcumin in the Modulation of TLR-4 Signaling Pathway: Focus on Neuroprotective and Anti-Rheumatic Properties. International journal of molecular sciences 54 32225104
2018 Structure-Activity Relationship in Monosaccharide-Based Toll-Like Receptor 4 (TLR4) Antagonists. Journal of medicinal chemistry 54 29494148
2006 Toll-like receptor (TLR) polymorphisms in African children: common TLR-4 variants predispose to severe malaria. The Journal of communicable diseases 54 17373355
2007 The toll-like receptor-4 (TLR-4) pathway and its possible role in the pathogenesis of Escherichia coli mastitis in dairy cattle. Veterinary research 53 18073092
2020 Mycoplasma pneumoniae lipids license TLR-4 for activation of NLRP3 inflammasome and autophagy to evoke a proinflammatory response. Clinical and experimental immunology 52 32894580
2014 Toll like receptor (TLR)-4 as a regulator of peripheral endogenous opioid-mediated analgesia in inflammation. Molecular pain 49 24499354
2019 Role of Nociceptor Toll-like Receptor 4 (TLR4) in Opioid-Induced Hyperalgesia and Hyperalgesic Priming. The Journal of neuroscience : the official journal of the Society for Neuroscience 48 31209174
2018 Schisandrin Attenuates Lipopolysaccharide-Induced Lung Injury by Regulating TLR-4 and Akt/FoxO1 Signaling Pathways. Frontiers in physiology 48 30177885
2017 Palmitate induces VSMC apoptosis via toll like receptor (TLR)4/ROS/p53 pathway. Atherosclerosis 47 28609685
2013 Modulation of CD14 and TLR4·MD-2 activities by a synthetic lipid A mimetic. Chembiochem : a European journal of chemical biology 47 24339336
2005 TLR-4 regulates CD8+ T cell trapping in the liver. Journal of immunology (Baltimore, Md. : 1950) 46 16034104
2021 TLR4 biased small molecule modulators. Pharmacology & therapeutics 45 34171331
2019 LPS-Binding Protein Modulates Acute Renal Fibrosis by Inducing Pericyte-to-Myofibroblast Trans-Differentiation through TLR-4 Signaling. International journal of molecular sciences 44 31357597
2014 TLR-4 signalling pathway: MyD88 independent pathway up-regulation in chicken breeds upon LPS treatment. Veterinary research communications 43 25417198
2014 TLR4 in Toxoplasmosis; friends or foe? Microbial pathogenesis 42 24685700
2021 Lactobacillus delbrueckii alleviates depression-like behavior through inhibiting toll-like receptor 4 (TLR4) signaling in mice. Annals of translational medicine 41 33842587
2021 Interaction of Opioids with TLR4-Mechanisms and Ramifications. Cancers 41 34771442
2022 Phytochemicals targeting Toll-like receptors 4 (TLR4) in inflammatory bowel disease. Chinese medicine 39 35484567
2015 A novel crosstalk between TLR4- and NOD2-mediated signaling in the regulation of intestinal inflammation. Scientific reports 39 26153766
2020 TLR-4 Signaling vs. Immune Checkpoints, miRNAs Molecules, Cancer Stem Cells, and Wingless-Signaling Interplay in Glioblastoma Multiforme-Future Perspectives. International journal of molecular sciences 38 32354122
2016 Endotoxaemia-augmented murine venous thrombosis is dependent on TLR-4 and ICAM-1, and potentiated by neutropenia. Thrombosis and haemostasis 38 27975098
2015 Postulates for validating TLR4 agonists. European journal of immunology 38 25476977
2017 Correlation of TLR4 and KLF7 in Inflammation Induced by Obesity. Inflammation 37 27714571
2017 Role of TLR4 signaling in the nephrotoxicity of heme and heme proteins. American journal of physiology. Renal physiology 35 28978536
2011 Genetic variation of TLR-4, TLR-9 and TIRAP genes in Iranian malaria patients. Malaria journal 34 21457584
2010 Toll-like receptor (TLR)-4 mediates anti-β2GPI/β2GPI-induced tissue factor expression in THP-1 cells. Clinical and experimental immunology 34 21091668
2024 Mechanistic insights on TLR-4 mediated inflammatory pathway in neurodegenerative diseases. Pharmacological reports : PR 32 38918327
2016 Toll-Like Receptor (TLR)4 and MyD88 are Essential for Atheroprotection by Peritoneal B1a B Cells. Journal of the American Heart Association 31 27930350
2019 TLR4 promotes liver inflammation by activating the JNK pathway. European review for medical and pharmacological sciences 29 31539158
2022 Atorvastatin suppresses NLRP3 inflammasome activation in intracerebral hemorrhage via TLR4- and MyD88-dependent pathways. Aging 28 35017318
2018 Placental inflammation by HMGB1 activation of TLR4 at the syncytium. Placenta 28 30501882
2006 TLR2 and TLR4 expression during bacterial infections. Current pharmaceutical design 28 17100621
2016 Stimulation through CD40 and TLR-4 Is an Effective Host Directed Therapy against Mycobacterium tuberculosis. Frontiers in immunology 27 27729911
2013 Nitric oxide boosts TLR-4 mediated lipocalin 2 expression in chondrocytes. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 27 23483583
2018 TLR4 Polymorphisms and Expression in Solid Cancers. Molecular diagnosis & therapy 25 30311146
2011 TLR4 and HMGB1: partners in crime? Kidney international 24 21841835
2016 Adsorbed Fibrinogen stimulates TLR-4 on monocytes and induces BMP-2 expression. Acta biomaterialia 23 27856281
2024 Echinatin alleviates inflammation and pyroptosis in hypoxic-ischemic brain damage by inhibiting TLR4/ NF-κB pathway. International immunopharmacology 22 38850784
2020 TLR4 Response to LPS Is Reinforced by Urokinase Receptor. Frontiers in immunology 22 33362762
2016 Imidacloprid induced histomorphological changes and expression of TLR-4 and TNFα in lung. Pesticide biochemistry and physiology 22 27265821
2020 Resveratrol attenuates TLR-4 mediated inflammation and elicits therapeutic potential in models of sepsis. Scientific reports 20 33139717
2012 TLR-4 expression and decrease in chronic inflammation: indicators of aggressive follicular thyroid carcinoma. Journal of clinical pathology 20 22267982
2015 Comparison of TLR-2, TLR-4, and antimicrobial peptide levels in different lesions of acne vulgaris. Cutaneous and ocular toxicology 19 26695933
2022 Cyanidin and delphinidin restore colon physiology in high fat diet-fed mice: Involvement of TLR-4 and redox-regulated signaling. Free radical biology & medicine 18 35691508
2021 Non-toxic sulfur inhibits LPS-induced inflammation by regulating TLR-4 and JAK2/STAT3 through IL-6 signaling. Molecular medicine reports 18 33907855
2016 Hyaluronan Inhibits Tlr-4-Dependent RANKL Expression in Human Rheumatoid Arthritis Synovial Fibroblasts. PloS one 18 27054952
2014 TLR-2 and TLR-4 expression in monocytes of newborns with late-onset sepsis. Jornal de pediatria 18 24878008
2023 Concomitant inhibition of TLR-4 and SGLT2 by phloretin and empagliflozin prevents diabetes-associated ischemic acute kidney injury. Food & function 17 37218423
2021 Toll-Like Receptor 4 (TLR4) and AMPK Relevance in Cardiovascular Disease. Advanced pharmaceutical bulletin 17 36721803
2019 TLR-2 and TLR-4 agonists favor expansion of CD4+ T cell subsets implicated in the severity of neuromyelitis optica spectrum disorders. Multiple sclerosis and related disorders 17 31229737
2018 Expression and function of TLR4- induced B1R bradykinin receptor on cardiac fibroblasts. Toxicology and applied pharmacology 17 29775649
2018 Influence of morphine on TLR4/ NF-kB signaling pathway of MCF-7 cells. Bratislavske lekarske listy 17 30113863
2014 Interactions of surface-expressed TLR-4 and endosomal TLR-9 accelerate lupus progression in anti-dsDNA antibody transgenic mice. Experimental biology and medicine (Maywood, N.J.) 17 24719374
2020 Tristetraprolin regulates necroptosis during tonic Toll-like receptor 4 (TLR4) signaling in murine macrophages. The Journal of biological chemistry 16 32094226
2020 The relationship among vitamin D, TLR4 pathway and preeclampsia. Molecular biology reports 16 32654051
2020 Scoparone alleviates hepatic fibrosis by inhibiting the TLR-4/NF-κB pathway. Journal of cellular physiology 16 33090488
2009 Toll-like receptor 4 (TLR4) and typhoid fever in Vietnam. PloS one 16 19277200

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