Affinage

TLR2

Toll-like receptor 2 · UniProt O60603

Length
784 aa
Mass
89.8 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TLR2 is a Toll/IL-1R-family pattern recognition receptor that initiates innate immune and inflammatory signaling, functioning as a cell-surface sensor whose engagement activates NF-κB and MAPK cascades (PMID:9596645, PMID:11254583, PMID:11521063). Ligand recognition occurs through heterodimerization with co-receptors: TLR1 and TLR2 form cotranslational heterodimers whose paired TIR domains constitute the critical intracellular signaling interface (PMID:12975352), and the synthetic agonist Diprovocim binds a hydrophobic pocket between two TLR2 ectodomains to drive both TLR2/TLR1 heterodimers and TLR2 homodimers (PMID:30829478). Co-receptor identity dictates adapter usage: the TLR1 TIR D-helix docks MyD88 while the TLR6 TIR D-helix recruits TIRAP/Mal (PMID:27150837), and the canonical MyD88→IRAK→TRAF6→NIK→IKK→NF-κB cascade drives proinflammatory gene induction such as IL-8 (PMID:11254583, PMID:11521063). Beyond this canonical route, the TLR2/TLR6 heterodimer couples Mal to the PI3K p85α subunit in a MyD88-independent manner to generate PIP3 and Akt-driven macrophage polarization (PMID:19574958), and TLR2 also evokes c-Src/PI3K/PLCγ/IP3R-dependent intracellular Ca²⁺ release (PMID:16818794). TLR2 senses endogenous danger signals including HMGB1, signaling through MyD88 to drive vWF expression via SP1 (PMID:27480067) and mesangial fibronectin deposition in lupus nephritis (PMID:31667864). Context-specific complexes extend its roles: a CD36/TLR2/TLR6 platelet complex transduces oxidized-phospholipid signals to promote thrombosis (PMID:28775078), sialylated TLR2 binds Siglec15 to initiate osteoclast fusion (PMID:35232979), and TLR2 binds NOX1/NOXO1 in endothelium to drive eNOS uncoupling and diet-induced endothelial dysfunction (PMID:34127487). Endothelial TLR2 further licenses P-selectin surface localization and adhesion-molecule upregulation to support inflammation, tumor angiogenesis, and immune recruitment (PMID:33986920).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 Medium

    Established that TLR2 is a functional signaling receptor, not merely an orphan membrane protein, by showing it activates NF-κB when expressed in cells.

    Evidence Functional NF-κB activation assay in transfected cells (cloned as TIL4)

    PMID:9596645

    Open questions at the time
    • No ligand identified at this stage
    • Single functional readout, foundational cloning only
  2. 2001 High

    Defined the canonical TLR2 signaling cascade by epistasis, ordering MyD88→IRAK→TRAF6/TRAF2→NIK→IKK→NF-κB to drive cytokine gene induction.

    Evidence Dominant-negative mutant overexpression with NF-κB reporter and IL-8 induction in HEK293/CD14 cells; parallel finding of distinct TLR2 vs TLR4 cytokine outputs and PI3K/p38 involvement in dendritic cells

    PMID:11254583 PMID:11477091 PMID:11521063

    Open questions at the time
    • Did not resolve co-receptor requirement
    • Adapter docking mechanism unmapped
  3. 2003 High

    Showed TLR2 activates p38 MAPK directly and that TLR1-TLR2 heterodimers, assembled via their TIR domains, are required for functional signaling, establishing receptor architecture.

    Evidence In vitro p38 kinase assay with ATF2 substrate; confocal colocalization, chimeric receptor epistasis and cross-linking of TLR1/TLR2

    PMID:11867688 PMID:12975352

    Open questions at the time
    • Did not distinguish TLR1 vs TLR6 functional differences
    • Ligand-induced conformational changes not resolved
  4. 2004 High

    Demonstrated genetically that TLR2 signaling requires MyD88 but can be independent of TLR4/TLR6 for specific ligands, and revealed dual pro- and anti-inflammatory outputs.

    Evidence Macrophages from TLR2, TLR4, TLR6, and MyD88 knockout mice stimulated with mycobacterial lipomannans

    PMID:15034058

    Open questions at the time
    • Mechanism of the MyD88-independent inhibitory effect undefined
  5. 2009 High

    Revealed heterodimer-specific adapter usage: TLR2/TLR6 couples Mal to PI3K p85α in a MyD88-independent branch driving Akt and macrophage polarization, whereas TLR2/1 does not.

    Evidence Reciprocal Co-IP of Mal with p85α, Akt/PIP3 assays in MyD88- and Mal-deficient cells

    PMID:19574958

    Open questions at the time
    • Structural basis of Mal-p85α docking not resolved
    • Did not map how heterodimer geometry selects this branch
  6. 2016 Medium

    Mapped the molecular basis of differential adapter recruitment, assigning the MyD88 docking site to the TLR1 TIR D-helix and the TIRAP site to the TLR6 TIR D-helix.

    Evidence Cell-permeable D-helix peptides blocking Co-IP of TLR2 with MyD88 or TIRAP; in vitro binding

    PMID:27150837

    Open questions at the time
    • Single lab, peptide-competition based
    • No co-crystal of the TIR-adapter interface
  7. 2006 Medium

    Established a non-transcriptional output of TLR2: c-Src/PI3K/PLCγ-dependent IP3R activation releasing intracellular Ca²⁺, broadening TLR2 signaling beyond NF-κB.

    Evidence Ca²⁺ flux and kinase inhibition studies in airway epithelium and TLR2-deficient macrophages

    PMID:16818794

    Open questions at the time
    • Direct c-Src phosphorylation site on TLR2 not defined
  8. 2017 High

    Identified a CD36/TLR2/TLR6 receptor complex transducing oxidized-phospholipid signals through TIRAP-MyD88-IRAK-TRAF6 to integrin activation, linking TLR2 to thrombosis.

    Evidence Co-IP of the platelet receptor complex, MyD88/TLR2/TLR6 knockouts, in vivo intravital thrombosis in ApoE-/- mice

    PMID:28775078

    Open questions at the time
    • Stoichiometry and assembly order of the CD36/TLR2/TLR6 complex unresolved
  9. 2019 Medium

    Showed TLR2 senses the endogenous danger signal HMGB1 through MyD88, driving SP1-dependent vWF transcription and mesangial fibronectin deposition, extending TLR2 to sterile inflammatory disease.

    Evidence TLR2 silencing/antibody blockade, HMGB1 and SP1 inhibitors, promoter binding assays; TLR2-/- and HMGB1-/- mouse disease models

    PMID:27480067 PMID:31667864

    Open questions at the time
    • Direct HMGB1-TLR2 binding affinity not measured
    • Co-receptor for HMGB1 sensing not defined
  10. 2019 High

    Structurally defined the TLR2 agonist-binding pocket using the synthetic agonist Diprovocim, confirming a hydrophobic inter-ectodomain pocket that drives dimerization.

    Evidence Crystal structure of Diprovocim-TLR2 ectodomain complex with biophysical dimerization assays

    PMID:30829478

    Open questions at the time
    • Does not capture full ternary TLR2/TLR1/MyD88 signaling assembly
    • Endogenous lipopeptide binding mode inferred not crystallized here
  11. 2022 High

    Uncovered glycosylation-dependent TLR2 function: ST3Gal1-mediated sialylation of TLR2 enables binding to Siglec15 to initiate osteoclast cell-cell fusion, a role distinct from pathogen sensing.

    Evidence Co-IP of Siglec15 with sialylated TLR2, ST3Gal1 knockdown, macrophage Siglec15 conditional knockout, in vivo sialidase injection

    PMID:35232979

    Open questions at the time
    • Whether this fusion role requires canonical TLR2 signaling is unaddressed
  12. 2021 High

    Demonstrated TLR2 forms a physical complex with NOX1/NOXO1 driving eNOS uncoupling, and that endothelial TLR2 licenses P-selectin and adhesion molecule expression, defining endothelial/vascular roles.

    Evidence Co-IP of TLR2 with NOX1/NOXO1, TLR2 reporter and endothelial-specific knockout mice, vascular and tumor models

    PMID:33986920 PMID:34127487

    Open questions at the time
    • Ligand triggering endothelial TLR2-NOX1 assembly in vivo not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct co-receptor pairings and context-specific partners (CD36, NOX1, Siglec15, Dectin-1, C5aR1) are integrated to select among the NF-κB, PI3K/Akt, Ca²⁺, and adhesion outputs of TLR2 remains unresolved.
  • No unified structural model of context-dependent TLR2 signalosomes
  • Quantitative rules linking receptor proximity/composition to output selection lacking

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
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-109582 Hemostasis 2
Partners
C5AR1CD36MYD88NOX1SIGLEC15TIRAPTLR1TLR6
Complex memberships
CD36/TLR2/TLR6 platelet complexTLR2/NOX1/NOXO1 complexTLR2/TLR1 heterodimerTLR2/TLR6 heterodimer

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 TLR2 (cloned as TIL4) activates NF-κB signaling when expressed in cells, establishing it as a functional signaling receptor of the Toll/IL-1R family involved in immune modulation. Functional NF-κB activation assay in transfected cells Blood Medium 9596645
2001 TLR2 activation by peptidoglycan and micrococci induces IL-8 transcription through a defined signaling cascade: TLR2 → MyD88 → IRAK → TRAF6/TRAF2 → NIK → IKK → NF-κB. Dominant-negative forms of each component blocked NF-κB activation and IL-8 gene induction. Dominant-negative mutant overexpression, NF-κB reporter assay, IL-8 gene expression in HEK293 cells expressing TLR2 and CD14 Infection and immunity High 11254583 11521063
2001 TLR2 and TLR4 agonists both activate NF-κB and MAPK family members in dendritic cells but produce distinct cytokine/chemokine profiles: TLR2 stimulation fails to induce IL-12 p70 and IP-10 but preferentially induces IL-12 p40 homodimer, IL-8, and IL-23; phosphatidylinositol 3-kinase and p38 MAPK are involved in TLR-mediated cytokine induction. Cytokine/chemokine gene transcription analysis, pharmacological inhibitors of PI3K and p38 MAPK in human dendritic cells stimulated with TLR2 or TLR4 agonists The Journal of biological chemistry Medium 11477091
2002 TLR2 expression in HEK293 cells enables phosphorylation and activation of stress-activated MAP kinase p38 in response to bacterial lipoproteins and Gram-positive bacteria, demonstrated by in vitro kinase assay using ATF2 as substrate and MAP kinase-activated protein kinase activation. TLR2 transfection in HEK293 cells, in vitro p38 kinase assay with ATF2 substrate, MAP kinase-activated protein kinase activation assay Journal of leukocyte biology Medium 11867688
2003 TLR1 and TLR2 form cotranslational heterodimeric complexes on the cell surface and in the cytosol (detected by confocal microscopy), and both the extracellular and intracellular (TIR) domains of each receptor are required for functional NF-κB signaling; the TIR domains constitute the critical intracellular TLR1-TLR2 interaction interface. Confocal microscopy of co-expressed tagged receptors, chimeric TLR analysis, cross-linking of surface receptors, NF-κB reporter assay, cytokine secretion from mononuclear cells The Journal of cell biology High 12975352
2003 TLR2 activation in murine macrophages requires MyD88 but is independent of TLR4 or TLR6 for LM-induced macrophage activation (CD40/CD86 expression, TNF, NO secretion). LM also exerts a TLR2/TLR6/MyD88-independent inhibitory effect on LPS-activated macrophages. Macrophages from TLR2, TLR4, TLR6, and MyD88 knockout mice stimulated with mycobacterial lipomannans; cytokine measurement, CD40/CD86 surface expression Journal of immunology High 15034058
2006 TLR2 ligands activate Ca²⁺ release from intracellular stores in airway epithelial cells and macrophages via a pathway involving TLR2 phosphorylation by c-Src, recruitment of PI3K and phospholipase Cγ, and activation of IP3 receptors. Absence of TLR2 abolishes Ca²⁺ fluxes and proinflammatory NF-κB-dependent signaling. Biochemical and genetic approaches in airway epithelial cells and TLR2-deficient murine macrophages; Ca²⁺ flux measurement, kinase inhibition studies Journal of immunology Medium 16818794
2007 TLR2 directly triggers IFN-γ production, cell proliferation, and cell survival in mouse Th1 effector cells without TCR stimulation; these effects were absent in Th2 cells and depended on enhanced MAPK activation. No other TLRs tested replicated this effect in Th1 cells. TLR stimulation of sorted Th1/Th2 effector T cells; cytokine measurement, proliferation and survival assays, MAPK phosphorylation analysis in wild-type and TLR2-deficient cells Journal of immunology Medium 17513716
2009 Upon stimulation of the TLR2/TLR6 heterodimer with diacylated bacterial lipoproteins, the adaptor Mal directly interacts with the PI3K regulatory subunit p85α in an inducible fashion, driving PI3K-dependent Akt phosphorylation, PIP3 generation, and macrophage polarization. This pathway is MyD88-independent, and TLR2/1 does not require Mal or MyD88 for Akt phosphorylation, revealing heterodimer-specific adapter usage. Co-immunoprecipitation of Mal with p85α, Akt phosphorylation assays, PIP3 measurement, macrophage polarization assays, MyD88-deficient and Mal-deficient cells The EMBO journal High 19574958
2010 TLR2 stimulation in keratinocytes triggers calcium-dependent release of the serine protease kallikrein 5; this was demonstrated using TLR2 overexpression, TLR2 ligand treatment, and analysis of TLR2-deficient mice, linking TLR2 to a critical pathogenic protease in rosacea. TLR2 overexpression in keratinocytes, TLR2 ligand stimulation, TLR2-deficient mouse analysis, calcium chelation, kallikrein 5 measurement The Journal of investigative dermatology Medium 21107351
2011 TLR2 stimulation in megakaryocytes activates NFκB, ERK-MAPK, and PI3K/Akt pathways, upregulates transcription factors GATA-1, NF-E2, and mTOR, increases DNA content and adhesion to extracellular matrix proteins, and promotes megakaryocyte maturation in a TLR2-dependent manner confirmed by TLR2 knockout mice. Pam3CSK4 stimulation of Meg-01 cells and mouse megakaryocytes; pathway inhibitors, gene/protein expression, TLR2-/- mice treated with Pam3CSK4 Blood Medium 21454454
2012 Phospholipase D2 (PLD2) and protein kinase C-η (PKC-η) act downstream of TLR2 (MyD88-dependent) to induce ABCA1 expression in macrophages; PLD2-generated phosphatidic acid is a key mediator of this effect. Pam3CSK4 stimulation, pathway inhibitors, MyD88-dependent signaling, direct diC8PA treatment in Raw264.7 macrophages; mRNA and protein quantification Biochemical and biophysical research communications Medium 23261454
2013 In TLR2-mediated gastric tumourigenesis, MyD88 but not Mal/TIRAP is required; genetic ablation of Myd88 suppressed tumourigenesis with increased apoptosis and reduced proliferation, whereas Mal deficiency had no effect on tumour burden. Mal is thus dispensable for TLR2-promoted gastric tumour growth. Genetic epistasis using gp130F/F mouse model with Myd88 and Mal knockout; tumour histology, apoptosis, proliferation, and pathway activation analysis Oncogene Medium 23728346
2015 TLR2 activation with Pam3CSK4 induces cell migration and invasion in rheumatoid arthritis synovial fibroblasts via β1-integrin binding and Rac1 activation, leading to cytoskeletal rearrangement and filopodia formation. Blocking β1-integrin inhibited Pam3CSK4-induced migration and invasion and Rac1 activation but not MMP-3 secretion. Transwell Matrigel invasion assay, Rac1 pull-down assay/Western blot, β1-integrin multiplex binding assay, F-actin immunofluorescence, anti-TLR2 mAb (OPN301) blocking, RA explant cultures Arthritis research & therapy Medium 26055925
2015 HCMV miR-UL112-3p directly targets TLR2 mRNA, reducing TLR2 protein levels and inhibiting TLR2/IRAK1/NFκB signaling. Down-regulation of endogenous TLR2 was confirmed by miR-UL112-3p mimic transfection, and was absent in cells infected with miR-UL112-3p-deficient HCMV mutants; miR-UL112-3p suppressed IL-1β, IL-6, IL-8, and NFκB-dependent luciferase activity upon TLR2 agonist stimulation. Luciferase reporter assay, miR mimic/siRNA transfection, HCMV miRNA-deficient mutant infection, immunoblot for TLR2 protein, NFκB reporter, IRAK1 phosphorylation, cytokine quantification PLoS pathogens High 25955717
2016 Differential adapter recruitment by TLR2 co-receptors: the D helix of TLR1 TIR domain is a MyD88 docking site, whereas the D helix of TLR6 TIR domain recruits TIRAP. Cell-permeable D-helix peptides from TLR1 or TLR6 selectively blocked co-immunoprecipitation of TLR2 with MyD88 or TIRAP respectively, without disrupting TLR2 co-receptor association. Cell-permeable TIR-domain peptides, co-immunoprecipitation of TLR2 with adapters TIRAP and MyD88, in vitro binding assays Pathogens and disease Medium 27150837
2017 TLR2 and TLR6 are required for platelet activation by oxidized phospholipids (oxPCCD36); oxPCCD36 induces formation of a CD36/TLR2/TLR6 complex in platelets and activates downstream signaling via TIRAP-MyD88-IRAK1/4-TRAF6, leading to integrin activation via the SFK-Syk-PLCγ2 pathway. TLR2 or TLR6 deficiency in ApoE-/- mice abrogated oxPCCD36-driven accelerated thrombosis. In vitro platelet activation assays, Co-IP of CD36/TLR2/TLR6 complex, genetic deletion of MyD88, TLR2, TLR6 in mice, intravital thrombosis studies in ApoE-/- mice Circulation research High 28775078
2019 Crystal structure of the synthetic TLR2/TLR1 agonist Diprovocim bound to TLR2 ectodomain revealed two Diprovocim molecules bound within the ligand-binding pocket formed between two TLR2 ectodomains, stabilized by extensive hydrophobic interactions and hydrogen-bonding. Diprovocim induced both TLR2/TLR1 heterodimers and TLR2 homodimers in vitro. Crystal structure determination of Diprovocim-TLR2 ectodomain complex, in vitro biophysical assays (heterodimer/homodimer formation), computational docking Journal of medicinal chemistry High 30829478
2019 TLR2 activation induces IL-6 expression and shedding of soluble IL-6 receptor (sIL-6R) from monocytes via the metalloproteases ADAM10 and ADAM17, and the ERK cascade differentially regulates both IL-6 and sIL-6R generation, triggering IL-6 trans-signaling. TLR2 stimulation of PBMCs and THP-1 cells; flow cytometry for TLR2/IL-6R co-expression; ADAM10/ADAM17 inhibitors; ERK pathway inhibition; ELISA for IL-6 and sIL-6R Scientific reports Medium 31086276
2019 TLR2 plays a pivotal role in mucosal serotonin (5-HT) production in the gut: TLR2-deficient and MyD88-deficient mice have lower enterochromaffin (EC) cell numbers and 5-HT levels; TLR2/1 agonist upregulates 5-HT production via NF-κB pathway in human EC cell line BON-1; T. muris excretory-secretory products induce 5-HT via TLR2. TLR2-/- and MyD88-/- mouse phenotyping, antibiotic depletion, irradiated mice reconstituted with Tlr2-/- bone marrow, germ-free mice, TLR2 agonist stimulation of BON-1 cells, NF-κB pathway assays, anti-TLR2 antibody blockade Journal of immunology Medium 30952815
2019 Nanoscale proximity (<500 nm centroid-to-centroid) between Dectin-1 and TLR2 on the same phagosome is required for their synergistic enhancement of macrophage immune responses; segregating the two receptors to opposite sides of a phagosome abolishes this signaling synergy without changing overall membrane composition. Patterned ligand particles for geometric manipulation of receptor colocalization on phagosomes; live cell imaging; cytokine readouts in macrophages Proceedings of the National Academy of Sciences Medium 31754039
2021 TLR2 physically binds NOX1 and NOXO1 in aortic endothelial cells upon BMP4 stimulation, and TLR2 knockout in mice abrogates high-fat diet-induced endothelial dysfunction (eNOS uncoupling, superoxide production) and metabolic features of type 2 diabetes. Co-immunoprecipitation of TLR2 with NOX1/NOXO1, TLR2 knockout mice on high-fat diet, eNOS coupling assays, superoxide measurement, NO bioavailability, vascular relaxation assays Diabetes Medium 34127487
2021 Endothelial TLR2 is highly expressed in the endothelium, promotes proinflammatory endothelial cell function, and is required for cell surface localization of P-selectin and subsequent upregulation of E-selectin, ICAM-1, and VCAM-1 for immune cell recruitment. Endothelial TLR2 promotes tumor growth, angiogenesis, and protumorigenic immune cell recruitment in a mouse prostate cancer model. TLR2-IRES-EGFP reporter mice, endothelial-specific TLR2 deletion, P-selectin localization assays, adhesion molecule protein measurements, syngeneic prostate tumor model, intravital imaging Science signaling High 33986920
2022 Sialyltransferase ST3Gal1 (induced by RANKL) sialylates TLR2, enabling binding of sialylated TLR2 to Siglec15 (expressed on M-CSF-stimulated macrophages). This Siglec15-sialylated TLR2 interaction initiates cell-cell recognition and fusion for osteoclast formation. Macrophage-specific Siglec15 deletion and intrafemoral sialidase injection abrogated osteoclast fusion. Co-immunoprecipitation of Siglec15 with sialylated TLR2, sialyltransferase ST3Gal1 knockdown, RANKL/M-CSF stimulation, Siglec15 conditional knockout in macrophages, intrafemoral sialidase injection, osteoclast fusion and bone formation assays Bone research High 35232979
2022 Atypical LPS from Ochrobactrum intermedium induces TLR4/TLR2 heterodimerization: molecular docking predicts a favorable TLR2/TLR4/MD-2 heterodimer complex, which was experimentally confirmed by FRET in cells. The core saccharide of LPS plays an important role in this interaction. Fluorescence resonance energy transfer (FRET) in cells, molecular docking, reporter assays for TLR2 and TLR4 signaling Frontiers in immunology Medium 35140704
2015 TLR2 activation by TLR1/2 agonist (Pam3CSK4) in neonatal mice induces TLR2- and MyD88-dependent leukocyte (mainly neutrophils and monocytes) infiltration into the CSF and brain, preferentially via the blood-CSF barrier (choroid plexus, subarachnoid space, median eminence), with a distinct hypothalamic chemokine response and increased blood-CSF barrier permeability not induced by TLR4 or TLR2/6 agonists. Intraperitoneal injection of TLR agonists in postnatal day 8 mice; flow cytometry of CSF and brain immune cells; radioactively labeled sucrose for barrier permeability; TLR2-/- and MyD88-/- mice Journal of leukocyte biology Medium 27493242
2016 TLR2 activation by ICV Pam3CSK4 triggers hypothalamic inflammation and activation of arcuate nucleus microglia, resulting in increased POMC neuronal activity and sickness behaviors (anorexia, hypoactivity, hyperthermia). NF-κB antagonists, cyclooxygenase pathway inhibitors, and melanocortin receptor 3/4 antagonists reversed the anorexia and body weight loss. Intracerebroventricular injection of Pam3CSK4; NF-κB, COX, and melanocortin receptor pharmacological blockade; POMC neuron activity measurement; hypothalamic cytokine analysis Scientific reports Medium 27405276
2015 PLAP-1/asporin physically binds both TLR2 and TLR4 (by immunoprecipitation) and negatively regulates TLR2- and TLR4-induced NF-κB activity and proinflammatory cytokine expression in macrophages and periodontal ligament cells; PLAP-1/asporin also reduced IκB kinase α degradation induced by TLR4. Immunoprecipitation assay, NF-κB reporter assay, cytokine ELISA, overexpression and recombinant protein addition, Western blot for IKKα Journal of dental research Medium 26399972
2019 HMGB1 upregulates von Willebrand Factor (vWF) expression via a TLR2-MYD88-SP1 pathway; TLR2 silencing completely blocked MYD88 expression, SP1 phosphorylation, and vWF upregulation, while SP1 binding to the vWF promoter was inhibited by TLR2 silencing or HMGB1 inhibition. Tlr2 siRNA silencing, HMGB1 inhibitor, SP1 inhibitor, TLR2-immunoneutralizing antibody, TLR2 agonist stimulation, chromatin/promoter binding assay for SP1, vWF expression in murine hypoxia model European journal of immunology Medium 27480067
2018 C5aR1 physically interacts with TLR2 in osteoblasts (demonstrated by co-immunoprecipitation), and C5aR1 and TLR2 signaling pathways converge on activation of p38 MAPK and generation of CXCL10, an osteoclastogenic factor. Whole-genome microarray, co-immunoprecipitation of C5aR1 and TLR2, p38 MAPK activation assay, CXCL10 measurement in osteoblasts Journal of cellular and molecular medicine Medium 30247799
2019 HMGB1 promotes glomerular mesangial matrix deposition (fibronectin release) in lupus nephritis via TLR2 and the MyD88/NF-κB pathway; inhibition of TLR2 or HMGB1 blocked fibronectin release and MyD88/NF-κB activation, and both TLR2- and HMGB1-deficient mice showed reduced proteinuria and improved glomerular histology. TLR2/HMGB1 inhibition in mesangial cell culture, TLR2-/- and HMGB1-/- mouse models, fibronectin/Western blot, NF-κB pathway analysis Journal of cellular physiology Medium 31667864
2020 TLR2/TLR1 heterodimers and TLR2/TLR6 heterodimers mediate distinct sensory neuron-driven behaviors: TLR2/1 (Pam3CSK4) evokes both pain and itch, whereas TLR2/6 (LTA, zymosan) produces only pain. Both effects require TRPV1 and TRPA1 channels, as demonstrated by calcium imaging in DRG neurons from TRPV1-/- and TRPA1-/- mice. TLR2 knockout mice, TRPV1/TRPA1 knockout mice, behavioral assays (pain/itch), DRG neuron calcium imaging with TLR2 agonists Neuroscience Medium 31954829
2015 TLR2 activation induces cPLA2α phosphorylation at Ser505 in synoviocytes, leading to arachidonic acid release and PGE2 production; cPLA2α inhibitors attenuated TLR2/1- and TLR2/6-induced AA release, PGE2, IL-6, IL-8, and COX2 expression. Exogenous PGE2 rescued IL-6 transcription blocked by cPLA2α inhibition, placing cPLA2α upstream of COX/PGE2 in TLR2-induced inflammation. cPLA2α inhibitors, AA release assay, PGE2 ELISA, cytokine gene/protein expression, COX1/2 inhibitors, PGE2 rescue experiment in synoviocytes PloS one Medium 25893499
2011 PI3K physically interacts with the glucocorticoid receptor (GR) through two YxxM motifs (at Tyr598 and Tyr663) in the GR, and this interaction is required for TLR2-triggered PI3K signaling that modulates TNFα production. Mutation of these tyrosines significantly reduced PI3K-GR interaction and GC effects on TLR2-induced TNFα expression, without altering GR transcriptional activity or localization. PI3K-dominant negative mutant, GR Tyr-to-Phe mutagenesis, co-immunoprecipitation of PI3K and GR, TNFα measurement upon Pam3CSK4 stimulation with/without dexamethasone, NF-κB/AP-1 reporter assays Journal of cellular and molecular medicine Medium 19874421

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells. The Journal of biological chemistry 523 11477091
2014 TLR2 and TLR4 in autoimmune diseases: a comprehensive review. Clinical reviews in allergy & immunology 312 24352680
2015 TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion. European heart journal 290 25755115
2010 TLR2 expression is increased in rosacea and stimulates enhanced serine protease production by keratinocytes. The Journal of investigative dermatology 272 21107351
2003 Toll-like receptor 2 (TLR2) and TLR4 differentially activate human mast cells. European journal of immunology 215 12672055
2004 Toll-like receptor 2 (TLR2)-dependent-positive and TLR2-independent-negative regulation of proinflammatory cytokines by mycobacterial lipomannans. Journal of immunology (Baltimore, Md. : 1950) 198 15034058
1998 Cloning and characterization of two Toll/Interleukin-1 receptor-like genes TIL3 and TIL4: evidence for a multi-gene receptor family in humans. Blood 182 9596645
2007 Cutting edge: TLR2 directly triggers Th1 effector functions. Journal of immunology (Baltimore, Md. : 1950) 172 17513716
2002 TLR2: cellular sensor for microbial and endogenous molecular patterns. Current topics in microbiology and immunology 160 12467248
2001 Micrococci and peptidoglycan activate TLR2-->MyD88-->IRAK-->TRAF-->NIK-->IKK-->NF-kappaB signal transduction pathway that induces transcription of interleukin-8. Infection and immunity 140 11254583
2003 Mycobacterial infection in TLR2 and TLR6 knockout mice. Microbiology and immunology 137 12825894
2013 TLR2 & Co: a critical analysis of the complex interactions between TLR2 and coreceptors. Journal of leukocyte biology 114 23990624
2010 Role of TLR2- and TLR4-mediated signaling in Mycobacterium tuberculosis-induced macrophage death. Cellular immunology 105 19919859
2014 Glioma-associated microglial MMP9 expression is upregulated by TLR2 signaling and sensitive to minocycline. International journal of cancer 99 24752463
2009 Mal connects TLR2 to PI3Kinase activation and phagocyte polarization. The EMBO journal 96 19574958
2003 Importance of extra- and intracellular domains of TLR1 and TLR2 in NFkappa B signaling. The Journal of cell biology 95 12975352
2011 Regulatory effects of TLR2 on megakaryocytic cell function. Blood 93 21454454
2007 Cancer relapse under chemotherapy: why TLR2/4 receptor agonists can help. European journal of pharmacology 93 17383632
2015 Human Cytomegalovirus miR-UL112-3p Targets TLR2 and Modulates the TLR2/IRAK1/NFκB Signaling Pathway. PLoS pathogens 91 25955717
2009 Roles of TLR2, TLR4, NOD2, and NOD1 in pulp fibroblasts. Journal of dental research 91 19734466
2008 Fungal Recognition by TLR2 and Dectin-1. Handbook of experimental pharmacology 79 18071656
2016 Hypothalamic TLR2 triggers sickness behavior via a microglia-neuronal axis. Scientific reports 74 27405276
2000 Role of MD-2 in TLR2- and TLR4-mediated recognition of Gram-negative and Gram-positive bacteria and activation of chemokine genes. Journal of endotoxin research 74 11521063
2014 TLR2 promoter hypermethylation creates innate immune dysbiosis. Journal of dental research 73 25389002
2019 Structural Basis of TLR2/TLR1 Activation by the Synthetic Agonist Diprovocim. Journal of medicinal chemistry 71 30829478
2006 Activation of Ca2+-dependent signaling by TLR2. Journal of immunology (Baltimore, Md. : 1950) 67 16818794
2013 Citrus flavonoid naringenin inhibits TLR2 expression in adipocytes. The Journal of nutritional biochemistry 66 23333096
2014 Targeting TLR2 for vaccine development. Journal of immunology research 64 25057505
2017 TLR2 Plays a Key Role in Platelet Hyperreactivity and Accelerated Thrombosis Associated With Hyperlipidemia. Circulation research 63 28775078
2012 Toll-like receptors (TLR2 and TLR4) recognize polysaccharides of Pseudallescheria boydii cell wall. Carbohydrate research 63 22507831
2015 Association of TLR1, TLR2, TLR4, TLR6, and TIRAP polymorphisms with disease susceptibility. Immunologic research 61 25784622
2020 TLR2 as a Therapeutic Target in Bacterial Infection. Trends in molecular medicine 57 32563557
2018 Costimulation through TLR2 Drives Polyfunctional CD8+ T Cell Responses. Journal of immunology (Baltimore, Md. : 1950) 56 30578304
2003 Porcine TLR2 and TLR6: identification and their involvement in Mycoplasma hyopneumoniae infection. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 53 14585198
2009 Expression of TLR2, TLR4, and TLR9 in dermatomyositis and polymyositis. Clinical rheumatology 52 19953283
2019 Activation of Toll-like Receptor 2 (TLR2) induces Interleukin-6 trans-signaling. Scientific reports 51 31086276
2013 Wnt5a, TLR2 and TLR4 are elevated in advanced human atherosclerotic lesions. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 51 24346141
2015 Toll-like receptor 2 (TLR2) induces migration and invasive mechanisms in rheumatoid arthritis. Arthritis research & therapy 48 26055925
2018 Phloretin as a Potent Natural TLR2/1 Inhibitor Suppresses TLR2-Induced Inflammation. Nutrients 47 29976865
2008 Pimecrolimus enhances TLR2/6-induced expression of antimicrobial peptides in keratinocytes. The Journal of investigative dermatology 47 18496569
2007 The Troll in Toll: Mal and Tram as bridges for TLR2 and TLR4 signaling. Journal of leukocyte biology 47 17449723
2013 Hypermethylation and low transcription of TLR2 gene in chronic periodontitis. Human immunology 45 23747679
2012 Toll-like receptor (TLR2 and TLR4) polymorphisms and chronic obstructive pulmonary disease. PloS one 45 22952638
2018 Screening of herbal extracts for TLR2- and TLR4-dependent anti-inflammatory effects. PloS one 44 30307962
2011 TLR2: a crossroads between infections and autoimmunity? International journal of immunopathology and pharmacology 44 21978687
2023 Bifidobacterium adolescentis induces Decorin+ macrophages via TLR2 to suppress colorectal carcinogenesis. Journal of experimental & clinical cancer research : CR 43 37464382
2002 Toll-like receptor 2 (TLR2) mediates activation of stress-activated MAP kinase p38. Journal of leukocyte biology 42 11867688
2021 Endothelial TLR2 promotes proangiogenic immune cell recruitment and tumor angiogenesis. Science signaling 41 33986920
2013 Leptin up-regulates TLR2 in human monocytes. Journal of leukocyte biology 41 23341537
2022 Induction of TLR4/TLR2 Interaction and Heterodimer Formation by Low Endotoxic Atypical LPS. Frontiers in immunology 40 35140704
2016 TLR2-mediated leukocyte trafficking to the developing brain. Journal of leukocyte biology 40 27493242
2013 Differential role of MyD88 and Mal/TIRAP in TLR2-mediated gastric tumourigenesis. Oncogene 40 23728346
2022 TLR2 Activation by Porphyromonas gingivalis Requires Both PPAD Activity and Fimbriae. Frontiers in immunology 39 35432342
2019 TLR2 Plays a Pivotal Role in Mediating Mucosal Serotonin Production in the Gut. Journal of immunology (Baltimore, Md. : 1950) 39 30952815
2019 Microglial activation by microbial neuraminidase through TLR2 and TLR4 receptors. Journal of neuroinflammation 39 31791382
2022 Sialylation of TLR2 initiates osteoclast fusion. Bone research 37 35232979
2021 Toll-Like Receptor 2 (TLR2) Knockout Abrogates Diabetic and Obese Phenotypes While Restoring Endothelial Function via Inhibition of NOX1. Diabetes 36 34127487
2019 DNA Methylation of Candidate Genes (ACE II, IFN-γ, AGTR 1, CKG, ADD1, SCNN1B and TLR2) in Essential Hypertension: A Systematic Review and Quantitative Evidence Synthesis. International journal of environmental research and public health 36 31805646
2010 Involvement of TLR2 and TLR4 in cell responses to Rickettsia akari. Journal of leukocyte biology 36 20616112
2018 C5aR1 interacts with TLR2 in osteoblasts and stimulates the osteoclast-inducing chemokine CXCL10. Journal of cellular and molecular medicine 35 30247799
2020 Role of TLR2 and TLR4 in regulation of articular chondrocyte homeostasis. Osteoarthritis and cartilage 34 32007503
2020 TLR2 agonists and their structure-activity relationships. Organic & biomolecular chemistry 34 32582902
2014 The crosstalk between TLR2 and NOD2 in Aspergillus fumigatus keratitis. Molecular immunology 34 25549945
2009 Rare TLR2 mutations reduce TLR2 receptor function and can increase atopy risk. Allergy 33 19220214
2019 Geometrical reorganization of Dectin-1 and TLR2 on single phagosomes alters their synergistic immune signaling. Proceedings of the National Academy of Sciences of the United States of America 32 31754039
2013 TLR2 and TLR4 in cutaneous leishmaniasis caused by Leishmania major. Scandinavian journal of immunology 32 23980810
2013 The role of TLR2 and 4 in Behçet's disease pathogenesis. Innate immunity 31 23940075
2012 Periodontopathogens induce expression of CD40L on human platelets via TLR2 and TLR4. Thrombosis research 31 22608210
2020 Activation of Different Heterodimers of TLR2 Distinctly Mediates Pain and Itch. Neuroscience 30 31954829
2015 PLAP-1/Asporin Regulates TLR2- and TLR4-induced Inflammatory Responses. Journal of dental research 30 26399972
2008 Regulation of TLR2 expression by prostaglandins in brain glia. Journal of immunology (Baltimore, Md. : 1950) 30 18523308
2006 TLR2 and TLR4 expression during bacterial infections. Current pharmaceutical design 28 17100621
2023 FFAR2 antagonizes TLR2- and TLR3-induced lung cancer progression via the inhibition of AMPK-TAK1 signaling axis for the activation of NF-κB. Cell & bioscience 27 37287005
2019 TLR2 promotes development and progression of human glioma via enhancing autophagy. Gene 27 30898699
2019 HMGB1 protein promotes glomerular mesangial matrix deposition via TLR2 in lupus nephritis. Journal of cellular physiology 27 31667864
2015 TLR2 deficiency attenuates skeletal muscle atrophy in mice. Biochemical and biophysical research communications 27 25749338
2016 Expression of TLR2 and TLR4 in murine small intestine during postnatal development. Bioscience, biotechnology, and biochemistry 26 27838962
2015 Necrosis-induced TLR3 Activation Promotes TLR2 Expression in Gingival Cells. Journal of dental research 26 26045329
2019 NLRC5 negatively regulates LTA-induced inflammation via TLR2/NF-κB and participates in TLR2-mediated allergic airway inflammation. Journal of cellular physiology 25 30945291
2012 TLR2 and TLR4 gene polymorphisms in Turkish vitiligo patients. Journal of the European Academy of Dermatology and Venereology : JEADV 25 22429552
2018 Enhanced TLR2 responses in multiple sclerosis. Clinical and experimental immunology 24 30043528
2015 Relationship of TLR2, TLR4 and tissue remodeling in chronic rhinosinusitis. International journal of clinical and experimental pathology 23 25973005
2016 Roles of Toll-Like Receptor 2 (TLR2), TLR4, and MyD88 during Pulmonary Coxiella burnetii Infection. Infection and immunity 22 26787722
2016 TLR2 and TLR4 polymorphisms in Southern Chinese Psoriasis Vulgaris patients. Journal of dermatological science 22 27155792
2020 Effect of Danshen on TLR2-triggered inflammation in macrophages. Phytomedicine : international journal of phytotherapy and phytopharmacology 21 32361291
2012 Mast cell TLR2 signaling is crucial for effective killing of Francisella tularensis. Journal of immunology (Baltimore, Md. : 1950) 21 22529298
2022 Keratinocyte TLR2 and TLR7 contribute to chronic itch through pruritic cytokines and chemokines in mice. Journal of cellular physiology 20 36436135
2018 Neutrophil CD64, TLR2 and TLR4 expression increases but phagocytic potential decreases during tuberculosis. Tuberculosis (Edinburgh, Scotland) 20 30029898
2016 HMGB1 facilitates hypoxia-induced vWF upregulation through TLR2-MYD88-SP1 pathway. European journal of immunology 20 27480067
2015 Cytosolic phospholipase A2 modulates TLR2 signaling in synoviocytes. PloS one 20 25893499
2009 Expression and Function of TLR2 on CD4 Versus CD8 T Cells. Immune network 20 20157599
2019 Toll-Like Receptor 2 (TLR2) and TLR4 Mediate the IgA Immune Response Induced by Mycoplasma hyopneumoniae. Infection and immunity 19 31611272
2017 Cell based assay identifies TLR2 and TLR4 stimulating impurities in Interferon beta. Scientific reports 19 28874687
2016 Differential adapter recruitment by TLR2 co-receptors. Pathogens and disease 19 27150837
2011 Phosphatidylinositol 3-kinase interacts with the glucocorticoid receptor upon TLR2 activation. Journal of cellular and molecular medicine 19 19874421
2005 Molecular cloning and tissue expression of canine Toll-like receptor 2 (TLR2). Veterinary immunology and immunopathology 19 16260044
2020 Polymorphisms of TLR2, TLR4 and TOLLIP and tuberculosis in two independent studies. Bioscience reports 18 32648572
2018 Mannose receptor (MR) and Toll-like receptor 2 (TLR2) influence phagosome maturation during Leishmania infection. Parasite immunology 18 29512160
2012 Expression of TLR2 and TLR4 in lesions of patients with tegumentary American leishmaniasis. Revista do Instituto de Medicina Tropical de Sao Paulo 18 22634888
2012 TLR2 stimulates ABCA1 expression via PKC-η and PLD2 pathway. Biochemical and biophysical research communications 18 23261454

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