Affinage

TLR5

Toll-like receptor 5 · UniProt O60602

Length
858 aa
Mass
97.8 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TLR5 is an innate immune pattern recognition receptor that senses bacterial flagellin and endogenous danger signals to activate pro-inflammatory and adaptive immune responses across epithelial barriers, dendritic cells, macrophages, neutrophils, and hepatocytes. Structural studies show that TLR5 recognizes the conserved D1 domain of flagellin via its lateral leucine-rich repeat surface, assembling a 2:2 tail-to-tail signaling complex that recruits the adaptor MyD88 through its TIR domain, activating NF-κB, p38 MAPK, PI3K/Akt, and STAT1 signaling cascades (PMID:22344444, PMID:15302888, PMID:17442957, PMID:18209032). TLR5 signaling is positively regulated by protein kinase D-mediated phosphorylation at S805 and negatively regulated by MUC1 cytoplasmic tail competition for MyD88 binding and by TRIF-induced caspase-dependent proteolytic degradation of TLR5 protein (PMID:17442957, PMID:22250084, PMID:20452988). Beyond innate immunity, TLR5 functions as a MyD88-independent endocytic receptor on dendritic cells that enhances MHC class II antigen presentation to CD4+ T cells, physically associates with TLR4 to bias MyD88-dependent signaling, and drives tissue-specific programs including intestinal homeostasis, osteoclast regulation, and hepatic ApoA1/HDL production (PMID:21182074, PMID:31989925, PMID:18008007, PMID:32820707).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1998 Medium

    Cloning of human TLR5 and demonstration that its overexpression activates NF-κB established it as a signaling-competent Toll-like receptor, but its ligand and physiological role were unknown.

    Evidence Cloning, Northern blot, NF-κB reporter assay in transfected cells

    PMID:9596645

    Open questions at the time
    • Ligand not yet identified
    • Adaptor usage unknown
    • In vivo relevance not demonstrated
  2. 2004 High

    Identification of flagellin as the TLR5 ligand and demonstration that signaling proceeds through MyD88 to activate NF-κB, MAPK, and SAPK pathways in intestinal epithelial cells established TLR5 as the principal flagellin sensor at mucosal surfaces.

    Evidence Dominant-negative TLR5 and MyD88 constructs, exogenous TLR5 expression in non-responsive cells, pathway kinase assays, polarized epithelial Ussing chamber ex vivo experiments

    PMID:15302888 PMID:15324458

    Open questions at the time
    • Structural basis of flagellin recognition unknown
    • Downstream signal branching not resolved
    • Co-factor requirements suggested but not identified
  3. 2005 Medium

    Discovery that TLR5 simultaneously activates pro-survival (NF-κB, PI3K/Akt) and pro-apoptotic (caspase-8) pathways revealed that TLR5 signaling outcome depends on the balance of parallel downstream cascades.

    Evidence Pharmacological inhibition of NF-κB and PI3K, caspase activation assays with TLR5-dependent controls

    PMID:16179598

    Open questions at the time
    • Physiological context determining survival vs. death choice unclear
    • Mechanism linking TLR5 to caspase-8 not defined
  4. 2007 High

    Identification of protein kinase D as a direct TLR5 interactor that phosphorylates S805 to enable p38-dependent IL-8 production provided the first post-translational regulatory mechanism for TLR5 activation.

    Evidence Co-immunoprecipitation, mass spectrometry phospho-site identification, S805A mutagenesis, shRNA knockdown of PKD

    PMID:17442957

    Open questions at the time
    • Whether S805 phosphorylation is required in all cell types unknown
    • Kinase(s) responsible for dephosphorylation not identified
  5. 2007 High

    TLR5-knockout mice developed spontaneous colitis rescued by concurrent TLR4 deletion, establishing TLR5 as essential for intestinal immune homeostasis and revealing genetic epistasis between TLR5 and TLR4.

    Evidence TLR5 KO and TLR4/TLR5 double-KO mice, histopathology, cytokine and bacterial load measurement

    PMID:18008007

    Open questions at the time
    • Cell type(s) in which TLR5 loss drives pathology not resolved
    • Whether TLR5-TLR4 epistasis reflects direct physical interaction unknown at this time
  6. 2009 High

    Demonstration that DC-intrinsic TLR5 is required for flagellin adjuvant activity and that intestinal lamina propria DCs selectively express TLR5 to drive IgA, Th17, and Th1 responses established TLR5 as a key bridge between innate and adaptive mucosal immunity.

    Evidence Bone marrow chimera mice, diphtheria toxin DC depletion, TLR5-KO infection models, adoptive CD4+ T cell transfer

    PMID:19494277 PMID:19547909

    Open questions at the time
    • How TLR5+ LPDC subset is specified developmentally unknown
    • Whether DC TLR5 signals differently from epithelial TLR5 not resolved
  7. 2010 Medium

    Three parallel advances defined negative regulation of TLR5 (TRIF-induced caspase-dependent degradation), a MyD88-independent endocytic antigen-presentation function, and cooperation with NLRC4 for full flagellin-driven adaptive immunity.

    Evidence TRIF overexpression with caspase inhibitor rescue and domain deletions; TLR5-KO DC presentation assays with MyD88-KO controls; TLR5/NLRC4 double-KO mice with antibody response measurement

    PMID:20452988 PMID:21072873 PMID:21182074

    Open questions at the time
    • Identity of the caspase(s) mediating TLR5 degradation not established
    • Structural basis of MyD88-independent endocytic function unknown
    • Relative contributions of TLR5 vs. NLRC4 in different tissues not quantified
  8. 2012 High

    Crystal structure of the TLR5–flagellin complex revealed a 2:2 tail-to-tail signaling architecture in which TLR5 engages the D1 domain helices via its lateral surface, providing the atomic basis for ligand recognition and dimerization-induced activation.

    Evidence 2.47 Å crystal structure of zebrafish TLR5–FliC complex with structure-guided mutagenesis and deletion validation

    PMID:22344444

    Open questions at the time
    • Human TLR5 structure not yet solved
    • How dimerization transmits signal across the membrane not determined
  9. 2012 High

    Discovery that MUC1 cytoplasmic tail competes with MyD88 for TLR5 binding upon EGFR-mediated phosphorylation defined a receptor-proximal negative regulatory mechanism linking growth factor and innate immune signaling.

    Evidence Reciprocal co-immunoprecipitation, MUC1-CT phospho-mutagenesis, MyD88 overexpression rescue, in vivo immunofluorescence

    PMID:22250084

    Open questions at the time
    • Whether MUC1 regulation of TLR5 operates in cell types beyond airway epithelia unknown
    • Stoichiometry of MUC1-TLR5 vs. MyD88-TLR5 complexes not defined
  10. 2016 Medium

    Identification of the endogenous danger molecule HMGB1 as a TLR5 ligand that activates MyD88-dependent NF-κB signaling expanded the TLR5 ligand repertoire beyond microbial flagellin to include sterile inflammation mediators.

    Evidence Biophysical binding assays, NF-κB reporter with MyD88 requirement, in vivo pain behavioral assays in TLR5-expressing tissues

    PMID:27760316

    Open questions at the time
    • Structural basis of HMGB1-TLR5 interaction not determined
    • Whether HMGB1-TLR5 signaling contributes to sterile inflammatory diseases in vivo not established
  11. 2017 High

    A higher-resolution Bacillus flagellin–TLR5 structure combined with alanine scanning identified a conserved hot spot (R89/E114/L93) fitting into TLR5 LRR9, refining the molecular pharmacophore for receptor activation.

    Evidence 2.1 Å crystal structure with systematic alanine scanning mutagenesis

    PMID:28106112

    Open questions at the time
    • Whether the hot spot is targetable pharmacologically unknown
    • Contribution of the D0 domain to activation mechanism remains structurally unresolved
  12. 2020 High

    Demonstration that TLR5 physically associates with TLR4 and biases TLR4 signaling toward MyD88 in macrophages, validated by human carriers of dominant-negative TLR5, resolved the earlier genetic epistasis and established TLR5 as a co-receptor modulating TLR4 responses.

    Evidence Co-immunoprecipitation of TLR5-TLR4, TLR5-KO mouse models challenged with LPS/ozone/hyaluronan, human TLR5 R392X carrier ex vivo studies

    PMID:31989925

    Open questions at the time
    • Whether TLR5-TLR4 heterodimer forms constitutively or is ligand-induced unclear
    • Structural basis of heterodimerization not solved
  13. 2020 Medium

    TLR5 signaling in hepatocytes drives ApoA1 transcription via NF-κB binding to the Apoa1 promoter, revealing a non-immune metabolic function for TLR5 in HDL biogenesis.

    Evidence TLR5-KO mice, hepatic TLR5 overexpression rescue, NF-κB ChIP on Apoa1 promoter, primary hepatocyte stimulation

    PMID:32820707

    Open questions at the time
    • Whether gut microbiota-derived flagellin is the physiological hepatic TLR5 stimulus in humans not established
    • Contribution relative to other ApoA1 transcriptional regulators unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the full-length human TLR5 structure (no solved structure exists), the mechanism of transmembrane signal transmission from ectodomain dimerization to TIR domain MyD88 recruitment, the structural basis of TLR5-TLR4 heterodimerization, and whether TLR5 endogenous ligands (HMGB1, α-synuclein) contribute to sterile inflammatory diseases in vivo.
  • Full-length human TLR5 structure not solved
  • Transmembrane signaling mechanism not established
  • Physiological relevance of non-flagellin ligands in disease contexts unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 6 GO:0060090 molecular adaptor activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-168256 Immune System 8 R-HSA-162582 Signal Transduction 7 R-HSA-5357801 Programmed Cell Death 2
Partners
HMGB1MUC1MYD88PRKD1TLR4TRAF6UNC93B1
Complex memberships
TLR5 homodimer (2:2 with flagellin)TLR5-TLR4 heteromeric complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 Crystal structure of zebrafish TLR5 in complex with Salmonella flagellin FliC D1/D2/D3 fragment at 2.47 Å resolution revealed that TLR5 interacts primarily with the three helices of the FliC D1 domain using its lateral side, and two TLR5-FliC 1:1 heterodimers assemble into a 2:2 tail-to-tail signaling complex stabilized by quaternary contacts of the FliC D1 domain with the convex surface of the opposing TLR5. Structure-guided mutagenesis and deletion analyses validated the signaling mechanism. Crystal structure (2.47 Å) + structure-guided mutagenesis and deletion analyses Science High 22344444
2017 Crystal structure of Bacillus subtilis flagellin (bsflagellin)–TLR5 complex at 2.1 Å resolution combined with alanine scanning identified a conserved hot spot in flagellin for TLR5 activation: an arginine residue (bsflagellin R89) and adjacent residues (E114 and L93) in the D1 domain provide shape and chemical complementarity to a cavity formed by the loop of leucine-rich repeat 9 in TLR5. The D0 domain also contributes to TLR5 activity through structurally dispersed regions. Crystal structure (2.1 Å) + alanine scanning mutagenesis of binding interface Scientific reports High 28106112
1998 Cloning of human TLR5 (designated TIL4) demonstrated that overexpression activates NF-κB in a cell-type-dependent fashion, establishing that TLR5 signals through the NF-κB pathway. Cloning, Northern blot tissue distribution, NF-κB reporter assay in transfected cells Blood Medium 9596645
2004 Flagellin activates NF-κB via TLR5 and also activates the MAPK, SAPK, and IKK signaling pathways in intestinal epithelial cells. Dominant-negative TLR5 alleles partially block flagellin-induced NF-κB activation, and exogenous TLR5 expression in non-responsive cells confers flagellin responsiveness, indicating TLR5 is necessary but that additional co-factors may be required for full signal propagation. Dominant-negative TLR5 overexpression, exogenous TLR5 expression in non-responsive cell lines, pathway kinase assays BMC microbiology Medium 15324458
2004 Commensal E. coli flagellin triggers NF-κB activation and proinflammatory chemokine (IL-8, CCL20) production in intestinal epithelial cells via TLR5 and the adaptor protein MyD88, as demonstrated by dominant-negative TLR5 and MyD88 constructs. In polarized epithelial cells, TLR5 mediates signaling from the apical surface in vivo. Dominant-negative TLR5 and MyD88 transfection, NF-κB reporter, Ussing chamber ex vivo, immunohistochemistry The Journal of biological chemistry High 15302888
2003 TLR5-mediated flagellin recognition activates p38 MAPK in a TLR5-dependent manner in polarized intestinal epithelia, and p38 MAPK pharmacological inhibition reduces IL-8 protein expression independently of NF-κB, indicating that TLR5 signals through a p38-dependent posttranscriptional mechanism to regulate IL-8 mRNA translation. Pharmacological p38 inhibition (SB-203580), phosphorylation assays, NF-κB reporter, mRNA stability assay American journal of physiology. Gastrointestinal and liver physiology Medium 12702497
2007 TLR5 deletion in mice results in spontaneous colitis characterized by decreased intestinal expression of TLR5-regulated host defense genes, elevated colonic bacterial burden, and increased hematopoietic-derived proinflammatory cytokines. Deletion of TLR4 rescues colitis in TLR5KO mice, demonstrating genetic epistasis: TLR4 drives colitis downstream of TLR5 deficiency. TLR5 knockout mouse model, TLR4/TLR5 double-knockout epistasis, histopathology, cytokine measurement, bacterial load quantification The Journal of clinical investigation High 18008007
2005 Flagellin-TLR5 interaction activates both proinflammatory (NF-κB, PI3K/Akt) and apoptotic (caspase 8 extrinsic pathway) signaling in epithelial cells. When NF-κB or PI3K/Akt is blocked, flagellin induces programmed cell death. Caspase 8 activation by purified flagellin is TLR5-dependent. Biochemical signaling assays, mRNA expression profiling, pharmacological inhibition of NF-κB and PI3K, caspase activation assays with TLR5-dependent controls American journal of physiology. Gastrointestinal and liver physiology Medium 16179598
2007 Chicken TLR5 (chTLR5) signals through MyD88 to activate NF-κB upon flagellin recognition. Mutagenesis of proline 737 in the chTLR5 TIR domain abrogated chTLR5 function, confirming TIR-domain-dependent MyD88 signaling. A single amino acid substitution (Q89A) in Salmonella Typhimurium flagellin abolished the species-specific TLR5 response. Targeted TIR domain mutagenesis, flagellin mutagenesis (Q89A), NF-κB reporter, confocal microscopy for expression Molecular immunology Medium 17964652
2007 Protein kinase D (PKD) directly interacts with TLR5 (co-immunoprecipitation), and this association is rapidly enhanced by flagellin. PKD phosphorylates TLR5 at serine 805 (identified by mass spectrometry); S805A mutation abrogates flagellin responses. PKD inhibition reduces IL-8 expression and prevents flagellin-induced p38 MAPK activation. shRNA-mediated PKD knockdown confirmed its role in p38-mediated IL-8 response to flagellin. Co-immunoprecipitation, mass spectrometry phospho-site identification, site-directed mutagenesis (S805A), pharmacological inhibition, shRNA knockdown Journal of immunology High 17442957
2010 TRIF (TIR domain containing adaptor-inducing IFN-β) induces proteolytic degradation of TLR5 protein via caspase activity, requiring the C-terminus of TRIF and the extracellular domain of TLR5. TRIF overexpression abolishes TLR5 protein levels without altering TLR5 mRNA, and dramatically suppresses flagellin/TLR5-driven NF-κB activation. This represents a post-translational regulatory mechanism for TLR5. TRIF overexpression, pan-caspase inhibitor rescue, domain deletion constructs (C-terminus of TRIF, extracellular domain TLR5), mRNA vs protein quantification The Journal of biological chemistry Medium 20452988
2012 MUC1 cytoplasmic tail associates with TLR5 in airway epithelial cells (HEK293T, A549, primary cells). EGFR activation by TGF-α phosphorylates the MUC1 cytoplasmic tail at Y46EKV, increasing MUC1/TLR5 association and competitively inhibiting MyD88 recruitment to TLR5, thereby suppressing downstream NF-κB and MAPK signaling. MUC1 overexpression inhibits flagellin-induced TLR5/MyD88 association. Co-immunoprecipitation, site-directed analysis of MUC1-CT phosphorylation, MyD88 overexpression rescue, in vivo immunofluorescence colocalization Journal of immunology High 22250084
2015 P. aeruginosa and flagellin activate EGFR in primary NHBE cells, leading to TGF-α release and EGFR-dependent tyrosine phosphorylation of the MUC1 cytoplasmic tail and increased MUC1-CT/TLR5 association, confirmed by co-immunoprecipitation. Co-immunoprecipitation of MUC1-CT with TLR5 and EGFR, ELISA for TGF-α, immunoblotting for EGFR phosphorylation Inflammation research Medium 26645913
2016 HMGB1 binds TLR5 and activates NF-κB signaling in a MyD88-dependent manner, resulting in proinflammatory cytokine production. The C-terminal tail region of HMGB1 is essential for TLR5 interaction. HMGB1-TLR5 signaling causes pain hypersensitivity in vivo. Biophysical binding assays, in vitro NF-κB reporter with MyD88 requirement, in vivo pain behavioral assays in TLR5-expressing cells Cell reports Medium 27760316
2006 Flagellin activates both TLR5 (NF-κB pathway) and the cell surface glycolipid asialoGM1. TLR5/Toll signaling is required for the release of ATP, and extracellular ATP is then required for Erk1/2 activation downstream of TLR5 — revealing that TLR5-induced Erk1/2 activation depends on autocrine nucleotide signaling through the asialoGM1 pathway. Pharmacological inhibition of lipid rafts vs. clathrin, ATP release assays, Erk1/2 phosphorylation assays, NF-κB reporter American journal of respiratory cell and molecular biology Medium 16439799
2010 TLR5 functions as an endocytic receptor on dendritic cells to enhance MHC class-II presentation of flagellin epitopes to CD4+ T cells, independent of MyD88. This was demonstrated using TLR5-deficient mice that failed to expand flagellin-specific CD4+ T cells even with additional TLR agonists, whereas processed flagellin peptide restored T-cell responses. TLR5-KO mouse immunization, MyD88-KO mice, in vitro DC flagellin presentation assay, adoptive T-cell transfer European journal of immunology Medium 21182074
2010 TLR5 signals through STAT1 to induce IFN-β production in bone marrow-derived macrophages upon flagellin stimulation. IFN-β then suppresses c-Fos protein expression and inhibits RANKL-induced osteoclastogenesis. STAT1 deficiency or JAK2 inhibition abolished flagellin-induced IFN-β and the anti-osteoclastogenic effect. IFN-β neutralizing antibody, STAT1 KO macrophages, JAK2 inhibitor, c-Fos western blot, osteoclast differentiation assay Journal of immunology Medium 18209032
2008 TLR5 activation by flagellin induces RANKL expression in osteoblasts via MyD88 and NF-κB, leading to robust osteoclast formation and bone loss both in vitro and in vivo. These effects were absent in Tlr5-/- mice. TLR5 KO mice, osteoblast/bone marrow culture, in vivo calvarial injection of flagellin, RANKL mRNA quantification FASEB journal Medium 26207027
2009 Direct stimulation of TLR5-expressing CD11c+ dendritic cells is required for the adjuvant activity of flagellin-OVA fusion protein. Using bone marrow chimeras and diphtheria toxin-mediated depletion, mice with TLR5-/- DC showed dramatically reduced antigen-specific CD4+ T cell responses. The adjuvant effect requires TLR5-MyD88 signaling as well as enhanced antigen uptake via TLR5. Bone marrow chimera mice, diphtheria toxin DC depletion, adoptive CD4+ T cell transfer, MyD88-/- TLR5+/+ mice Journal of immunology High 19494277
2009 Intestinal CD11c+ lamina propria dendritic cells (LPDCs) specifically express TLR5 but not TLR4, and respond to pathogenic flagellated bacteria to induce IgA+ plasma cell differentiation and Th17/Th1 cell differentiation. Transport of Salmonella from intestinal tract to mesenteric lymph nodes was impaired in Tlr5-/- mice, suggesting LPDCs expressing TLR5 are exploited by S. typhimurium for systemic spread. TLR5 KO mouse infection model, LPDC subset characterization, B cell/T cell differentiation assays Journal of gastroenterology Medium 19547909
2010 Flagellin-induced promotion of humoral immunity requires either TLR5 (activating NF-κB) or NLRC4 (activating the inflammasome). In TLR5/NLRC4 double-KO mice, all flagellin-induced cytokines and antibody responses were absent, demonstrating genetic epistasis: both receptors act in parallel to drive adaptive immunity to flagellin. TLR5 KO, NLRC4 KO, and TLR5/NLRC4 double-KO mice, cytokine measurement (KC/CXCL1, IL-18), antibody response measurement European journal of immunology High 21072873
2014 TLR5 activation by flagellin on dendritic cells induces IL-22 production, which drives a protective gene expression program in intestinal epithelial cells against rotavirus. NLRC4 activation by flagellin induces IL-18 and immediate elimination of RV-infected cells. Both TLR5 and NLRC4 are required for flagellin-mediated protection, and administration of IL-22 + IL-18 fully recapitulates flagellin protection. TLR5 KO, NLRC4 KO mice, cytokine neutralization/administration, adaptive immunity-independent model Science High 25395539
2010 TLR5 activation by flagellin induces secretory IL-1 receptor antagonist (sIL-1Ra) in intestinal epithelial cells and macrophages in a TLR5-dependent manner on non-hematopoietic cells. In TLR5KO mice, loss of sIL-1Ra increases the IL-1β/sIL-1Ra ratio, correlating with increased inflammatory pathology on flagellin treatment and Salmonella infection. TLR5 KO mice, bone marrow chimeras to distinguish hematopoietic vs. non-hematopoietic TLR5, cytokine ELISA, in vivo infection model Mucosal immunology Medium 20844479
2008 TLR5 is stored intracellularly in neutrophils and mobilized to the cell surface in a protein synthesis-independent manner through protein kinase C activation, or after stimulation with TLR ligands and cytokines. TLR1/TLR2 signaling via Pam3CSK4 is the most potent inducer of surface TLR5 expression. TLR5 surface mobilization enhances neutrophil phagocytic capacity and respiratory burst activity via IL-8/CXCR1 signaling. Confocal microscopy, flow cytometry, protein kinase C inhibitors, TLR1/TLR2 antibody blocking experiments, neutrophil functional assays Journal of immunology Medium 18684966
2020 TLR5 physically associates with TLR4 in primary murine macrophages (co-immunoprecipitation) and biases TLR4 signaling toward the MyD88-dependent pathway. In vivo, TLR5 deficiency reduces responses to LPS, hyaluronan, and ozone (TLR4-mediated stimuli). Human carriers of a dominant-negative TLR5 allele show decreased inflammatory responses to LPS and ozone. Co-immunoprecipitation of TLR5 with TLR4, in vivo TLR5 KO mouse models (LPS, O3, hyaluronan), human dominant-negative TLR5 allele carrier ex vivo studies eLife High 31989925
2019 H. pylori T4SS component CagL contains a flagellin D1-like motif that activates TLR5 in a flagellin-independent manner. CagL mediates adherence to TLR5+ epithelial cells and activates downstream TLR5 signaling. TLR5 KO mice show reduced control of H. pylori infection. In vitro TLR5 activation assays, TLR5 KO mouse infection model, human biopsy analysis Nature communications Medium 31844047
2018 Zebrafish TLR5 unexpectedly signals as a heterodimer composed of drTLR5b and drTLR5a gene products, not as a homodimer. Flagellin-induced signaling by the zebrafish heterodimer is enhanced by the TLR trafficking chaperone UNC93B1. TLR5 activation requires a heterodimeric configuration of both the ectodomain and cytoplasmic domain. Structure-guided substitution of the principal flagellin-binding site in human TLR5 with zebrafish TLR5 residues abrogated human TLR5 activation. Genetic domain-swap experiments (ectodomain and TIR domain swaps), UNC93B1 co-expression, structure-guided mutagenesis of human TLR5 flagellin-binding site PNAS High 29555749
2018 NME3 (nucleoside diphosphate kinase 3) is a positive regulator of TLR5-induced NF-κB signaling, acting mechanistically downstream of MyD88. Identified via genome-wide siRNA kinase library screen; confirmed by targeted knockdown and overexpression in carcinoma cells with NF-κB bioluminescent reporter. High-throughput siRNA kinase library screen, targeted knockdown and overexpression validation, NF-κB bioluminescent reporter, MyD88 epistasis Molecular cancer research Medium 29523766
2006 TLR5 stop codon polymorphism R392X and missense variants D694G and L822F are functionally relevant, abrogating flagellin-induced TLR5 signaling in transfected CHO-K1 cells. The common R392X (11.9% prevalence) acts as a dominant-negative allele. Transient transfection of TLR5 SNP variants in CHO-K1 cells, NF-κB reporter assay upon flagellin stimulation Human mutation Medium 16470719
2020 TLR5 activation by flagellin in hepatocytes stimulates ApoA1 production through transcriptional activation via NF-κB binding to the Apoa1 promoter. Hepatic TLR5 overexpression in TLR5-KO mice partially restored ApoA1 and HDL-C levels, confirming liver-cell-intrinsic TLR5 signaling in ApoA1/HDL metabolism. TLR5 KO mice, hepatic TLR5 overexpression rescue, NF-κB ChIP on Apoa1 promoter, primary hepatocyte stimulation, oral flagellin supplementation in Apoe-/- mice Circulation research Medium 32820707
2013 TLR5-mediated flagellin signaling in intestinal epithelial cells induces Notch1 and Jagged1 expression, and Notch1 synergistically enhances TLR5-mediated NF-κB activation via RBP-Jκ-dependent mechanism. Blocking Notch during acute colitis ameliorated inflammation, revealing a TLR5-Notch crosstalk in intestinal epithelium. Luciferase reporter assay for NF-κB, γ-secretase inhibitor, in vitro RBP-Jκ responsive element analysis of IL-6 promoter, in vivo Notch blocking in colitis model International journal of molecular medicine Low 24048326
2009 IL-8 induction by flagellin in A549 human alveolar epithelial cells requires lipid raft formation (inhibited by nystatin but not clathrin inhibitor chlorpromazine) and activation of intracellular TLR5, as TLR5 was found predominantly in the intracellular compartment of A549 cells rather than on the cell surface. Lipid raft inhibition (nystatin), clathrin inhibition (chlorpromazine), confocal microscopy for TLR5 subcellular localization, transient transfection NF-κB reporter Molecular immunology Medium 19786303
2014 Flagellin-induced TLR5 signaling activates NF-κB in myometrium via MyD88/TRAF6/NF-κB pathway. siRNA knockdown of TLR5, MyD88, or TRAF6 decreased flagellin-induced pro-inflammatory cytokines (IL-6, IL-8), MMP-9, COX-2, and prostaglandin release in human fetal membranes and myometrium. siRNA knockdown of TLR5, MyD88, TRAF6 in primary human cells; NF-κB luciferase reporter; ELISA cytokine measurement American journal of reproductive immunology Medium 24635133
2021 α-Synuclein monomers and oligomers activate the NLRP3 inflammasome in microglia via TLR5 (among other receptors). TLR5 ligation by α-synuclein contributes to NLRP3 activation at a distinct signaling checkpoint, and NLRP3 inhibition or deficiency improved α-synuclein clearance. Primary microglia from WT mice, TLR5 receptor involvement tested alongside TLR2, NLRP3 inhibitor (CRID3), NLRP3 KO mice, internalization and degradation assays Journal of immunology Low 34507948

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Structural basis of TLR5-flagellin recognition and signaling. Science (New York, N.Y.) 451 22344444
2007 Deletion of TLR5 results in spontaneous colitis in mice. The Journal of clinical investigation 351 18008007
2007 Potent immunogenicity and efficacy of a universal influenza vaccine candidate comprising a recombinant fusion protein linking influenza M2e to the TLR5 ligand flagellin. Vaccine 304 18063235
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
2014 Viral infection. Prevention and cure of rotavirus infection via TLR5/NLRC4-mediated production of IL-22 and IL-18. Science (New York, N.Y.) 181 25395539
2004 Flagellin acting via TLR5 is the major activator of key signaling pathways leading to NF-kappa B and proinflammatory gene program activation in intestinal epithelial cells. BMC microbiology 170 15324458
2004 In vitro and ex vivo activation of the TLR5 signaling pathway in intestinal epithelial cells by a commensal Escherichia coli strain. The Journal of biological chemistry 152 15302888
2003 TLR5-mediated activation of p38 MAPK regulates epithelial IL-8 expression via posttranscriptional mechanism. American journal of physiology. Gastrointestinal and liver physiology 127 12702497
2011 Age-associated elevation in TLR5 leads to increased inflammatory responses in the elderly. Aging cell 126 22023165
2017 A conserved TLR5 binding and activation hot spot on flagellin. Scientific reports 124 28106112
2010 TLR4 and TLR5 on corneal macrophages regulate Pseudomonas aeruginosa keratitis by signaling through MyD88-dependent and -independent pathways. Journal of immunology (Baltimore, Md. : 1950) 122 20826748
2016 HMGB1 Activates Proinflammatory Signaling via TLR5 Leading to Allodynia. Cell reports 118 27760316
2010 TLR5 signaling stimulates the innate production of IL-17 and IL-22 by CD3(neg)CD127+ immune cells in spleen and mucosa. Journal of immunology (Baltimore, Md. : 1950) 113 20566828
2004 Activation of TLR3 and TLR5 in channel catfish exposed to virulent Edwardsiella ictaluri. Developmental and comparative immunology 111 15854683
2005 Flagellin/TLR5 responses in epithelia reveal intertwined activation of inflammatory and apoptotic pathways. American journal of physiology. Gastrointestinal and liver physiology 109 16179598
2010 TLR5 or NLRC4 is necessary and sufficient for promotion of humoral immunity by flagellin. European journal of immunology 108 21072873
2007 Functional characterization of chicken TLR5 reveals species-specific recognition of flagellin. Molecular immunology 101 17964652
2010 Polymorphisms in the TLR4 and TLR5 gene are significantly associated with inflammatory bowel disease in German shepherd dogs. PloS one 96 21203467
2007 Altered inflammatory responses in TLR5-deficient mice infected with Legionella pneumophila. Journal of immunology (Baltimore, Md. : 1950) 95 17982089
2021 Microglial NLRP3 Inflammasome Activation upon TLR2 and TLR5 Ligation by Distinct α-Synuclein Assemblies. Journal of immunology (Baltimore, Md. : 1950) 85 34507948
2011 Induction of TLR-2 and TLR-5 expression by Helicobacter pylori switches cagPAI-dependent signalling leading to the secretion of IL-8 and TNF-α. PloS one 85 21573018
2010 TLR5 functions as an endocytic receptor to enhance flagellin-specific adaptive immunity. European journal of immunology 75 21182074
2022 Roseburia intestinalis stimulates TLR5-dependent intestinal immunity against Crohn's disease. EBioMedicine 73 36182776
2009 Direct stimulation of tlr5+/+ CD11c+ cells is necessary for the adjuvant activity of flagellin. Journal of immunology (Baltimore, Md. : 1950) 73 19494277
2008 TLR expression on neutrophils at the pulmonary site of infection: TLR1/TLR2-mediated up-regulation of TLR5 expression in cystic fibrosis lung disease. Journal of immunology (Baltimore, Md. : 1950) 73 18684966
2009 Immune responses of TLR5(+) lamina propria dendritic cells in enterobacterial infection. Journal of gastroenterology 72 19547909
2008 Innate immunity mediated by TLR5 as a novel antiinflammatory target for cystic fibrosis lung disease. Journal of immunology (Baltimore, Md. : 1950) 72 18490781
2012 TLR5, a novel and unidentified inflammatory mediator in rheumatoid arthritis that correlates with disease activity score and joint TNF-α levels. Journal of immunology (Baltimore, Md. : 1950) 67 22661088
2006 Biased distribution of single nucleotide polymorphisms (SNPs) in porcine Toll-like receptor 1 (TLR1), TLR2, TLR4, TLR5, and TLR6 genes. Immunogenetics 67 16604477
2019 T4SS-dependent TLR5 activation by Helicobacter pylori infection. Nature communications 65 31844047
2010 TLR5 activation induces secretory interleukin-1 receptor antagonist (sIL-1Ra) and reduces inflammasome-associated tissue damage. Mucosal immunology 65 20844479
2020 TLR5 participates in the TLR4 receptor complex and promotes MyD88-dependent signaling in environmental lung injury. eLife 62 31989925
2014 Microneedle delivery of an M2e-TLR5 ligand fusion protein to skin confers broadly cross-protective influenza immunity. Journal of controlled release : official journal of the Controlled Release Society 61 24417966
2014 The TLR2 ligand FSL-1 and the TLR5 ligand Flagellin mediate pro-inflammatory and pro-labour response via MyD88/TRAF6/NF-κB-dependent signalling. American journal of reproductive immunology (New York, N.Y. : 1989) 61 24635133
2014 Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice. Cellular & molecular immunology 61 25418468
2010 TLR5 as an anti-inflammatory target and modifier gene in cystic fibrosis. Journal of immunology (Baltimore, Md. : 1950) 61 21068401
2014 Crystal structure of FliC flagellin from Pseudomonas aeruginosa and its implication in TLR5 binding and formation of the flagellar filament. Biochemical and biophysical research communications 58 24434155
2014 Flagellin induces antibody responses through a TLR5- and inflammasome-independent pathway. Journal of immunology (Baltimore, Md. : 1950) 57 24442437
2013 Airway structural cells regulate TLR5-mediated mucosal adjuvant activity. Mucosal immunology 57 24064672
2005 Fish soluble Toll-like receptor (TLR)5 amplifies human TLR5 response via physical binding to flagellin. Vaccine 57 16314010
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2008 Stimulation by TLR5 modulates osteoclast differentiation through STAT1/IFN-beta. Journal of immunology (Baltimore, Md. : 1950) 50 18209032
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2007 Blocking of the TLR5 activation domain hampers protective potential of flagellin DNA vaccine. Journal of immunology (Baltimore, Md. : 1950) 41 17617608
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