Affinage

TLR5

Toll-like receptor 5 · UniProt O60602

Length
858 aa
Mass
97.8 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TLR5 is a Toll/IL-1R-family pattern recognition receptor that senses bacterial flagellin to drive innate immune signaling (PMID:9596645). Crystal structures of the flagellin–TLR5 complex establish that TLR5 engages three helices of the flagellin D1 domain through its lateral surface, with a conserved activation hot-spot arginine fitting a cavity formed by the leucine-rich repeat 9 loop, and that two 1:1 heterodimers assemble into a 2:2 tail-to-tail signaling complex (PMID:22344444, PMID:28106112). Surface display of TLR5 on immune cells requires the chaperone PRAT4A (PMID:22836022), and signaling competence depends on protein kinase D–mediated phosphorylation at serine 805 (PMID:17442957). Ligand engagement recruits MyD88 to activate NF-κB and, via a parallel arm, p38 MAPK that controls IL-8 output post-transcriptionally (PMID:12702497, PMID:15302888); TLR5 simultaneously engages a caspase-8 extrinsic apoptotic pathway held in check by NF-κB and PI3K-Akt survival signaling (PMID:16179598). In the intestinal epithelium TLR5 induces secretory IL-1Ra to counterbalance NLRC4/inflammasome-derived IL-1β (PMID:20844479), regulates tight-junction proteins and barrier resistance (PMID:28146004), and on lamina propria and CD11c+ dendritic cells drives Th17 differentiation, IL-22 production, and antibody/plasma-cell responses to flagellin (PMID:25220212, PMID:26907705, PMID:37742185). TLR5 also acts as an endocytic receptor that enhances MHC class II presentation of flagellin independently of MyD88 (PMID:21182074), physically associates with TLR4 to bias TLR4 signaling toward MyD88 (PMID:31989925), and is activated by non-flagellin ligands including HMGB1 and the H. pylori T4SS protein CagL (PMID:27760316, PMID:31844047). Genetic loss of TLR5 causes spontaneous TLR4-driven colitis (PMID:18008007), and the receptor additionally couples flagellin sensing to osteoclastogenesis through RANKL induction (PMID:26207027) and to hepatic ApoA1/HDL production via NF-κB (PMID:32820707). TLR5 transcription is set by the Sp1/Sp3 balance through PKC-ERK signaling in response to butyrate (PMID:27060138), and TLR5 protein is negatively regulated by TRIF-induced caspase-dependent degradation (PMID:20452988).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1998 Medium

    Established TLR5 as a functional innate immune receptor by showing it activates NF-κB, placing it in the Toll/IL-1R signaling family before its ligand was known.

    Evidence Cloning and NF-κB reporter assay in transfected cells

    PMID:9596645

    Open questions at the time
    • No ligand identified at this stage
    • Cell-type dependence of signaling unexplained
    • No downstream effectors mapped
  2. 2003 High

    Resolved how flagellin/TLR5 controls IL-8, showing a NF-κB-independent p38 MAPK arm that regulates IL-8 at the translational level.

    Evidence Dominant-negative TLR5, p38 inhibitor, mRNA stability assays in polarized intestinal epithelium

    PMID:12702497

    Open questions at the time
    • Link between p38 and translational machinery not defined
    • ERK activation not TLR5-specific
  3. 2004 High

    Defined the core adaptor and output of TLR5 signaling and its apical/basolateral geometry in epithelium, establishing MyD88-dependent NF-κB induction of chemokines.

    Evidence Dominant-negative TLR5/MyD88, NF-κB reporter, Ussing chamber and IHC in tissue; confocal localization in gastric biopsies

    PMID:15147355 PMID:15302888

    Open questions at the time
    • Functional consequence of polarized relocalization not directly tested
    • Mechanism of basolateral targeting unknown
  4. 2005 High

    Revealed that TLR5 simultaneously engages pro-survival and apoptotic programs, explaining how flagellin sensing is buffered against epithelial death.

    Evidence Caspase assays, pathway inhibitors, dominant-negative TLR5 in intestinal epithelial cells

    PMID:16179598

    Open questions at the time
    • Molecular link from TLR5 to caspase-8 not defined
    • In vivo relevance of the apoptotic arm untested here
  5. 2007 High

    Identified PKD as a direct kinase phosphorylating TLR5 at S805 required for responses, and extended TLR5 flagellin sensing to macrophages and species-specific TIR-domain signaling.

    Evidence Co-IP, in vitro kinase assay/MS, S805A mutagenesis, shRNA; TLR5-KO macrophages with flagellin-deficient bacterial strains; TIR-domain mutagenesis

    PMID:17442957 PMID:17964652 PMID:17982089

    Open questions at the time
    • How S805 phosphorylation gates MyD88 recruitment not resolved
    • Structural basis of species-specific flagellin recognition not solved
  6. 2008 High

    Showed TLR5 signaling can be anti-osteoclastogenic via an IFN-β/STAT1 axis, demonstrating context-dependent outputs beyond classical NF-κB inflammation.

    Evidence BMDM osteoclastogenesis assays, IFN-β neutralization, STAT1-KO cells, c-Fos rescue

    PMID:18209032

    Open questions at the time
    • Opposing osteoclast-promoting effect in co-culture mechanistically unexplained
    • Connection between TLR5 and IFN-β induction not mapped
  7. 2007 High

    Demonstrated by genetic epistasis that TLR5 loss causes spontaneous colitis that is TLR4-dependent, defining TLR5 as a homeostatic regulator of intestinal inflammation.

    Evidence TLR5-KO and TLR4/TLR5 double-KO mice, histopathology and cytokine profiling

    PMID:18008007

    Open questions at the time
    • Mechanism linking TLR5 loss to TLR4 hyperactivation not defined here
    • Microbiota contribution not dissected
  8. 2010 High

    Separated TLR5's signaling and antigen-presentation roles and defined surface-expression and negative-regulation requirements, showing endocytic MHC-II presentation, PRAT4A-dependent surface display, and TRIF/caspase-mediated TLR5 degradation.

    Evidence TLR5-KO/MyD88-KO mice with peptide vs whole flagellin; PRAT4A siRNA and anti-TLR5 mAb; TRIF overexpression with domain mapping and protease inhibitors

    PMID:20452988 PMID:21182074 PMID:22836022

    Open questions at the time
    • Endocytic trafficking machinery for TLR5 not identified
    • Physiological trigger for TRIF-driven TLR5 degradation unknown
  9. 2010 High

    Defined the division of labor between TLR5 and the NLRC4 inflammasome in flagellin immunity, with TLR5 driving NF-κB cytokines and sIL-1Ra while NLRC4 produces IL-1β/IL-18.

    Evidence TLR5-KO, NLRC4-KO, double-KO mice; bone marrow chimeras; immunization and cytokine/antibody measurements

    PMID:20844479 PMID:21072873

    Open questions at the time
    • Coordination between the two pathways at the cellular level not fully resolved
    • Source-specific contributions across tissues incompletely mapped
  10. 2012 High

    Provided the atomic mechanism of flagellin recognition, showing lateral-surface engagement of the flagellin D1 domain and assembly of a 2:2 tail-to-tail signaling complex.

    Evidence X-ray crystallography of zebrafish TLR5–FliC at 2.47 Å with structure-guided mutagenesis

    PMID:22344444

    Open questions at the time
    • Cytoplasmic TIR-domain dimerization upon activation not captured
    • Human full-length receptor structure not solved
  11. 2014 High

    Connected TLR5 to systemic and mucosal adaptive immunity, showing microbiota flagellin sensing is required for vaccine antibody responses and that DC TLR5/IL-22 cooperates with NLRC4/IL-18 for antiviral epithelial protection; structural confirmation extended flagellin recognition across species.

    Evidence TLR5-KO, germ-free/antibiotic and reconstitution mice (influenza vaccine); TLR5-KO/NLRC4-KO mice with IL-22/IL-18 rescue (rotavirus); P. aeruginosa FliC crystal structure with binding assays

    PMID:24434155 PMID:25220212 PMID:25395539

    Open questions at the time
    • How gut flagellin signal reaches systemic plasma cells not fully traced
    • P. aeruginosa TLR5 complex modeled, not solved
  12. 2015 High

    Extended TLR5 function to bone biology, showing flagellin/TLR5 induces RANKL in osteoblasts via MyD88/NF-κB to drive osteoclastogenesis and bone loss.

    Evidence TLR5-KO mice, calvarial and osteoblast cultures, in vivo flagellin injection, NF-κB inhibition

    PMID:26207027

    Open questions at the time
    • Reconciliation with anti-osteoclastogenic IFN-β arm not addressed
    • Relevance to inflammatory bone disease not established
  13. 2016 High

    Broadened TLR5 ligand repertoire to the endogenous alarmin HMGB1 and defined transcriptional control of TLR5 by Sp1/Sp3, plus a DC-intrinsic Th17-inducing role.

    Evidence HMGB1 binding/signaling assays and in vivo pain model; promoter reporter, ChIP, Sp1/Sp3 siRNA and PKC/ERK inhibitors; TLR5-KO LPDC co-culture

    PMID:26907705 PMID:27060138 PMID:27760316

    Open questions at the time
    • Structural basis of HMGB1–TLR5 interaction unknown
    • Whether endogenous ligand sensing uses the same activation hot-spot untested
  14. 2018 Medium

    Established the dimerization architecture in zebrafish (heterodimeric TLR5a/TLR5b) and identified intracellular regulators (MAP1S, NME3) of TLR5 signaling amplitude.

    Evidence Heterodimer co-expression, domain swaps, UNC93B1 co-transfection; siRNA kinase screen with NME3 validation; MAP1S knockdown with autophagy/MyD88 readouts; bovine PI3K-motif mutagenesis

    PMID:24466264 PMID:29247203 PMID:29523766 PMID:29555749

    Open questions at the time
    • MAP1S/NME3 mechanisms are single-lab
    • Generalizability of zebrafish heterodimeric mode to other species limited
  15. 2019 High

    Showed TLR5 is activated by the non-flagellin H. pylori T4SS protein CagL through a D1-like motif, expanding pathogen recognition beyond flagellin.

    Evidence Binding/NF-κB assays, siRNA, TLR5-KO mice infection model, human biopsy IHC

    PMID:31844047

    Open questions at the time
    • Structural detail of CagL–TLR5 engagement not solved
    • Whether CagL uses the canonical activation hot spot untested
  16. 2020 Medium

    Revealed a cross-receptor role in which TLR5 physically partners with TLR4 to bias signaling toward MyD88, and a metabolic role in hepatic ApoA1/HDL production.

    Evidence Co-IP in primary macrophages, TLR5-KO mouse LPS/hyaluronan/ozone models, human dominant-negative allele; TLR5-KO mice with liver-specific AAV rescue and Apoa1 promoter ChIP

    PMID:31989925 PMID:32820707

    Open questions at the time
    • TLR4/TLR5 co-IP is single-lab without structural validation
    • Stoichiometry of the TLR4–TLR5 association unknown
  17. 2022 High

    Placed TLR5 in tolerogenic and barrier-protective circuits, showing commensal-driven TLR5 induces epithelial TSLP that promotes Treg differentiation and DC/IL-22-mediated barrier protection.

    Evidence TLR5-siRNA Caco-2, Tlr5-/- and BM chimera mice, anti-TSLP/TGFβ neutralization, DC-T cell co-culture; conditional CD11c-MyD88-KO and AhR-KO mice with IL-22 readouts

    PMID:36182776 PMID:37742185

    Open questions at the time
    • Direct epithelial signaling steps from TLR5 to TSLP transcription not mapped
    • Interplay with AhR pathway mechanistically incomplete
  18. 2021 Medium

    Linked TLR5 to neuroinflammation, showing α-synuclein sensing by TLR5 (with TLR2) activates the NLRP3 inflammasome in microglia and impairs α-syn clearance.

    Evidence Primary microglia, antibody blocking, NLRP3 inhibitor and NLRP3-KO cells, α-syn degradation assays

    PMID:34507948

    Open questions at the time
    • Direct α-syn–TLR5 binding not demonstrated
    • Distinct TLR2 vs TLR5 checkpoints not molecularly defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How activated human full-length TLR5 transduces signal across the membrane—linking the 2:2 ectodomain complex, S805 phosphorylation, and TIR-domain assembly to MyD88 recruitment, and how it discriminates flagellin from endogenous/non-flagellin ligands—remains unresolved.
  • No structure of the activated TIR-domain signaling module
  • Mechanism connecting ectodomain dimerization to MyD88 recruitment unknown
  • Whether non-flagellin ligands trigger the same conformational pathway untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 4 GO:0060089 molecular transducer activity 4 GO:0038024 cargo receptor activity 1
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 5 R-HSA-5357801 Programmed Cell Death 1
Partners
HMGB1MYD88PRAT4APRKD1TLR4

Evidence

Reading pass · 38 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 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 FliC D1 with the convex surface of the opposing TLR5. Structure-guided mutagenesis and deletion analyses validated this signaling mechanism. X-ray crystallography (2.47 Å), structure-guided mutagenesis, deletion analysis Science High 22344444
2017 Crystal structure of Bacillus subtilis flagellin–TLR5 complex at 2.1 Å resolution combined with alanine scanning revealed a conserved TLR5 activation hot spot: an arginine residue (bsflagellin R89) and adjacent residues (E114, L93) in the flagellin 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. X-ray crystallography (2.1 Å), alanine scanning mutagenesis Scientific reports High 28106112
1998 TLR5 (cloned as TIL3) was identified as a human Toll/IL-1R-like receptor that activates NF-κB in a cell-type-dependent fashion, establishing its role in innate immune signaling. Cloning, NF-κB reporter functional assay in transfected cells Blood Medium 9596645
2003 Flagellin activates p38 MAPK in a TLR5-dependent manner in polarized intestinal epithelial cells, and this p38 activation regulates IL-8 expression by a post-transcriptional (translational) mechanism independent of NF-κB. ERK1/2 activation by flagellin was not TLR5-specific. Pharmacological inhibition of p38 MAPK (SB-203580), dominant-negative TLR5 transfection, mRNA stability assay, IL-8 protein/mRNA measurement American journal of physiology. Gastrointestinal and liver physiology High 12702497
2004 Flagellin released by commensal E. coli activates NF-κB, IL-8, and CCL-20 expression in intestinal epithelial cells via TLR5 and the adaptor protein MyD88. In polarized cells, TLR5 signaling could be triggered from the apical side; in vivo, flagellin on the mucosal side of ileal biopsies induced basolateral KC production. Dominant-negative TLR5 and MyD88 plasmid transfection, NF-κB reporter assay, ELISA, Ussing chamber ex vivo, immunohistochemistry The Journal of biological chemistry High 15302888
2005 Flagellin interaction with TLR5 on intestinal epithelial cells activates both NF-κB/PI3K-Akt pro-survival pathways and the extrinsic caspase-8 apoptotic pathway. When NF-κB or PI3K/Akt signaling is blocked, flagellin induces apoptosis, demonstrating that TLR5 simultaneously activates intertwined inflammatory and apoptotic signaling. Biochemical signaling assays, caspase activity assays, pharmacological pathway inhibition, mRNA expression profiling, dominant-negative TLR5 American journal of physiology. Gastrointestinal and liver physiology High 16179598
2007 Mice lacking TLR5 (TLR5KO) develop spontaneous colitis associated with decreased intestinal expression of TLR5-regulated host defense genes and increased colonic proinflammatory cytokines. Deletion of TLR4 in TLR5KO mice rescues colitis, establishing by genetic epistasis that TLR5 loss leads to TLR4-driven colitis. TLR5 knockout mouse model, TLR4/TLR5 double-knockout genetic epistasis, histopathology, cytokine measurement, bacterial burden quantification The Journal of clinical investigation High 18008007
2007 Protein kinase D (PKD) physically interacts with TLR5, and this association is rapidly enhanced by flagellin. PKD phosphorylates TLR5 at serine 805 (identified by in vitro phosphorylation and mass spectrometry); mutation of S805 to alanine abrogates flagellin responses. PKD is required for flagellin-induced p38 MAPK activation and IL-8 production in epithelial cells. Co-immunoprecipitation, in vitro kinase assay, mass spectrometry (S805 phosphorylation), site-directed mutagenesis (S805A), pharmacological inhibition (Gö6976), shRNA knockdown Journal of immunology High 17442957
2007 Chicken TLR5 (chTLR5) signals through the MyD88 pathway to activate NF-κB in response to flagellin; mutation of proline 737 in the chTLR5 TIR domain abrogates function. A single amino acid in flagellin (Q89) determines species-specific TLR5 responses between chicken, human, and mouse. Expression in HeLa cells, NF-κB reporter assay, site-directed mutagenesis of TIR domain (P737) and flagellin (Q89A, L415A, N100A) Molecular immunology Medium 17964652
2007 TLR5-deficient alveolar macrophages (AMs) fail to produce TNF-α after stimulation with Legionella pneumophila or purified flagellin, demonstrating that AMs recognize L. pneumophila via TLR5-mediated flagellin sensing. In vivo, TLR5-deficient mice show impaired early neutrophil recruitment (at 4 h) and later develop organizing pneumonia. TLR5 knockout mice, L. pneumophila infection model, bronchoalveolar lavage cell counts, TNF-α measurement, flagellin-deficient bacterial strain (LpFlaA-) comparison Journal of immunology High 17982089
2008 TLR5 activation by flagellin suppresses RANKL-induced osteoclastogenesis by stimulating IFN-β production through STAT1 activation in bone marrow-derived macrophages. IFN-β downregulates c-Fos protein (post-translationally), and neutralizing IFN-β or STAT1 deficiency reverses the anti-osteoclastogenic effect. In osteoblast–macrophage co-cultures, flagellin instead promotes osteoclast differentiation without inducing IFN-β. Bone marrow-derived macrophage culture, RANKL osteoclastogenesis assay, IFN-β neutralizing antibody, STAT1-knockout cells, JAK2 inhibitor (AG490), ectopic c-Fos and NFATc1 overexpression Journal of immunology High 18209032
2006 AsialoGM1 and TLR5 cooperate in flagellin signaling: TLR5 is required for NF-κB activation, while flagellin-induced ATP release (via Toll signaling) is required for Erk1/2 activation and mucin induction downstream of asialoGM1. TLR5 alone cannot activate Erk1/2 without extracellular ATP. Pharmacological inhibition, dominant-negative Toll signaling, ATP receptor signaling assays, Erk1/2 phosphorylation measurement in lung epithelial cells 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 peptides to CD4+ T cells independently of the MyD88 adaptor. TLR5-deficient mice show poor flagellin-specific CD4+ T cell expansion even when other TLR agonists are provided, but robust responses occur when pre-processed flagellin peptide is used. TLR5-knockout mice, flagellin peptide vs. whole flagellin immunization, in vitro DC culture system, adoptive transfer, MyD88-knockout comparison European journal of immunology High 21182074
2010 TLR5 activation induces secretory IL-1 receptor antagonist (sIL-1Ra) in intestinal epithelia and macrophages in a TLR5-dependent manner (on non-hematopoietic cells), whereas IL-1β production from flagellin depends on IPAF (inflammasome). Loss of TLR5 increases the IL-1β/sIL-1Ra ratio and correlates with increased inflammatory pathology. TLR5-knockout mice, bone marrow chimera experiments to identify non-hematopoietic source of sIL-1Ra, Salmonella infection model, ELISA Mucosal immunology High 20844479
2010 TLR5 or NLRC4 is necessary and sufficient for flagellin-mediated humoral immunity: TLR5-KO mice lack NF-κB-regulated cytokines (CXCL1) but retain IL-18, NLRC4-KO mice show the opposite pattern, and double-KO mice lack all cytokines and antibody responses to flagellin. TLR5-KO, NLRC4-KO, and TLR5/NLRC4 double-KO mice, prime/boost immunization, cytokine ELISA, antibody titer measurement European journal of immunology High 21072873
2010 TRIF induces proteolytic degradation of TLR5 protein through caspase activity (blocked by pan-caspase inhibitor but not by cathepsin B, ROS, or proteasome inhibitors), requiring the C-terminus of TRIF and the extracellular domain of TLR5. TRIF overexpression suppresses flagellin/TLR5-driven NF-κB activation without altering TLR5 mRNA levels. TRIF overexpression in HEK293 and NCM460 cells, caspase/cathepsin inhibitors, proteasome inhibitor, domain deletion constructs, Western blot, NF-κB reporter assay The Journal of biological chemistry Medium 20452988
2012 Cell surface expression of TLR5 on immune cells (macrophages, neutrophils, classical monocytes, specific DC subsets) is completely dependent on the TLR-specific chaperone PRAT4A. Silencing PRAT4A abolishes both surface TLR5 expression and flagellin-induced responses in the macrophage cell line J774. Anti-mouse TLR5 monoclonal antibody development, flow cytometry, PRAT4A siRNA silencing, cytokine ELISA, in vivo immune cell subset analysis International immunology High 22836022
2016 HMGB1 binds TLR5 and activates NF-κB signaling in a MyD88-dependent manner, resulting in proinflammatory cytokine production and pain hypersensitivity in vivo. The C-terminal tail region of HMGB1 is essential for the interaction with TLR5. Biophysical binding assays, NF-κB reporter assay in TLR5-expressing cells, MyD88-dependence testing, in vivo allodynia model, domain mapping of HMGB1 Cell reports Medium 27760316
2019 H. pylori T4SS component CagL contains a D1-like flagellin motif that mediates direct binding to TLR5, activating TLR5-dependent downstream signaling in gastric epithelial cells independently of flagellin. TLR5 is important for efficient control of H. pylori infection in vivo (TLR5-knockout vs. wild-type mice). TLR5 binding assays, NF-κB reporter assay, siRNA knockdown, TLR5-knockout mice, H. pylori infection model, human biopsy immunohistochemistry Nature communications High 31844047
2020 TLR5 physically associates with TLR4 in primary murine macrophages (co-immunoprecipitation) and biases TLR4 signaling towards the MyD88 pathway. TLR5 impacts in vivo responses to LPS, hyaluronan, and ozone (TLR4-mediated stimuli), and human carriers of a dominant-negative TLR5 allele show decreased inflammatory responses to these stimuli. Co-immunoprecipitation, TLR5-knockout mice in vivo models (LPS, O3, hyaluronan), human dominant-negative TLR5 allele carrier studies eLife Medium 31989925
2014 Crystal structure of P. aeruginosa FliC flagellin (paFliC) at 2.1 Å, combined with gel filtration and native PAGE, demonstrated direct TLR5 binding. Structural modeling shows the paFliC D1 domain provides major TLR5-binding sites analogous to Salmonella FliC. X-ray crystallography (2.1 Å), gel filtration, native PAGE, structural modeling of TLR5 complex Biochemical and biophysical research communications Medium 24434155
2018 Zebrafish TLR5 signals as a heterodimer composed of drTLR5b and drTLR5a (products of a duplicated gene), unlike mammalian TLR5 which signals as a homodimer. Flagellin-induced signaling requires both a heterodimeric ectodomain and cytoplasmic domain configuration; TLR5 trafficking chaperone UNC93B1 enhances signaling. Structure-guided substitution of the principal flagellin-binding site in human TLR5 with zebrafish TLR5 residues abrogated human TLR5 activation. Heterodimer co-expression and signaling assays, domain swap mutagenesis, UNC93B1 co-transfection, structure-guided site-directed mutagenesis of human TLR5 Proceedings of the National Academy of Sciences High 29555749
2014 TLR5-mediated sensing of gut microbiota flagellin is required for antibody responses to trivalent inactivated influenza vaccine (TIV): TLR5-KO mice have reduced antibody titers and fewer plasma cells. Mechanistically, TLR5 sensing promotes plasma cell differentiation directly and by stimulating lymph node macrophages to produce plasma cell growth factors. TLR5-KO mice, germ-free and antibiotic-treated mice, reconstitution with flagellated vs. aflagellated E. coli, plasma cell frequency measurement, antibody titer ELISA Immunity High 25220212
2014 Flagellin-induced protection against rotavirus requires both TLR5 (on dendritic cells) and NLRC4. TLR5 activation on DCs elicits IL-22 production which induces a protective gene expression program in intestinal epithelial cells; NLRC4 drives IL-18-dependent elimination of RV-infected cells. Administration of IL-22 and IL-18 together fully recapitulates flagellin protection. TLR5-KO and NLRC4-KO mice, flagellin treatment, rotavirus infection model, cytokine neutralization, IL-22 and IL-18 co-administration rescue experiment Science High 25395539
2016 TLR5 expression in intestinal epithelial cells is regulated at the transcriptional level by differential binding of Sp1 and Sp3 to GC-box sequences in the TLR5 promoter. Butyrate activates two PKC isoforms: one dephosphorylates/acetylates Sp1 (causing its displacement) and another phosphorylates Sp3 via ERK-MAPK, leading to Sp3 binding, p300 recruitment, histone acetylation, and TLR5 transcriptional activation. Promoter reporter assays, ChIP, siRNA knockdown of Sp1/Sp3, PKC isoform-specific inhibitors, ERK-MAPK inhibition, HDAC inhibition, mutagenesis of GC-box elements Nucleic acids research High 27060138
2015 TLR5 activation by flagellin induces RANKL expression in osteoblasts via a MyD88- and NF-κB-dependent mechanism, leading to robust osteoclast formation and bone loss in vitro and in vivo. These effects are absent in Tlr5-/- mice, establishing TLR5 as a direct activator of RANKL and osteoclastogenesis. TLR5-KO mice, neonatal calvarial bone culture, isolated osteoblast culture, local flagellin injection model, RANKL:OPG ratio measurement, osteoclast quantification, NF-κB inhibition FASEB journal High 26207027
2010 TLR5 requires the trafficking chaperone PRAT4A for cell surface expression; without PRAT4A, TLR5 is not expressed on the cell surface and flagellin-induced cytokine responses are abolished. PRAT4A-dependent surface TLR5 is primarily found on neutrophils, CD11b(hi)Ly6C(hi) classical monocytes, and specific DC subsets in vivo. Anti-TLR5 monoclonal antibody, PRAT4A siRNA silencing, flow cytometry, IL-6/G-CSF ELISA International immunology High 22836022
2020 TLR5 activation by flagellin in hepatocytes stimulates ApoA1 production through NF-κB transcriptional activation at the Apoa1 promoter. Deletion of hepatic TLR5 suppresses HFD-stimulated HDL-C and ApoA1 levels; overexpression of TLR5 in the liver of TLR5-KO mice partially restores ApoA1 and HDL-C production. TLR5-KO mice, liver-specific TLR5 overexpression (AAV), primary hepatocyte stimulation, NF-κB ChIP on Apoa1 promoter, fecal microbiome transplantation, HDL-C/ApoA1 ELISA Circulation research High 32820707
2017 TLR5 signaling in bovine cells requires PI3K activation for downstream responses; mutation of bTLR5 F798 (within a putative PI3K motif) to hTLR5 Y798 significantly reduces signaling. Species-specific TLR5 responses involve cognate MyD88 recognition differences between bovine and human TIR domains. Bovine vs. human TLR5 expression in cognate cell lines, siRNA knockdown, PI3K inhibitor, site-directed mutagenesis of TIR domain (F798Y), CXCL8 measurement Scientific reports Medium 29247203
2013 TLR5 epithelial activation by flagellin results in decreased epithelial barrier resistance and altered tight junction protein (claudin-3, occludin, ZO-1) expression in ileal tissue of SAMP mice. The elevated TLR5 in this model is derived primarily from non-hematopoietic (epithelial) cells, as demonstrated by bone marrow chimera experiments. Bone marrow chimera experiments, TLR5-specific ex vivo activation of ileal tissue, transepithelial resistance measurement, tight junction protein expression (claudin-3, occludin, ZO-1) Inflammatory bowel diseases Medium 28146004
2014 TLR5 signaling in myometrial and fetal membrane cells promotes pro-inflammatory cytokines (IL-6, IL-8), MMP-9, COX-2, and prostaglandin release through MyD88, TRAF6, and NF-κB. siRNA knockdown of TLR5, MyD88, TRAF6, or NF-κB inhibitor reduced flagellin-induced pro-labour mediator production. siRNA knockdown of TLR5, MyD88, TRAF6 in primary amnion and myometrium cells, NF-κB reporter assay, ELISA for cytokines, MMP-9 activity assay American journal of reproductive immunology Medium 24635133
2016 TLR5 mediates CD172α+ lamina propria DC (LPDC) induction of Th17 cells in the intestine in response to commensal flagellin. Wild-type CD172α+ LPDCs (but not TLR5-deficient LPDCs) induced Th17 cells when cultured with full-length flagellin; LPDCs expressed high levels of TLR5 and produced IL-23, IL-6, and TGFβ upon flagellin stimulation. TLR5-KO mice, microbiota antigen-specific T cell reporter mouse system, LPDC-T cell co-culture, flagellin vs. flagellin peptide comparison, cytokine measurement Scientific reports High 26907705
2018 MAP1S regulates the flagellin/TLR5 signaling pathway in breast cancer cells through enhancement of NF-κB activity and cytokine secretion. Knockdown of MAP1S abrogates flagellin-induced tumor suppression. MAP1S in later stages of TLR5 signaling degrades MyD88 via autophagy, providing a negative feedback mechanism. MAP1S knockdown (siRNA), NF-κB reporter assay, tumor growth assay, autophagy assay, MyD88 protein level measurement PloS one Medium 24466264
2018 Nucleoside diphosphate kinase 3 (NME3) is a positive regulator of TLR5-mediated NF-κB signaling, acting downstream of MyD88. Knockdown of NME3 reduces flagellin-induced NF-κB activation; overexpression enhances it. High-throughput siRNA library screen (691 kinases), NFκB bioluminescent reporter, NME3 targeted knockdown and overexpression validation Molecular cancer research Medium 29523766
2021 TLR5 ligation by α-synuclein monomers and oligomers (along with TLR2) activates the NLRP3 inflammasome in primary microglia, compromising α-syn degradation. TLR2 and TLR5 act on different signaling checkpoints of NLRP3 activation; NLRP3 inhibition improves overall clearance of α-syn oligomers. Primary microglia from wild-type mice, TLR2/TLR5 antibody blocking, NLRP3 inhibitor (CRID3), NLRP3-deficient cells, α-syn internalization and degradation assays Journal of immunology Medium 34507948
2022 Roseburia intestinalis stimulates TSLP production in intestinal epithelial cells specifically through TLR5 (not TLR2 or TLR4). TSLP from IECs induces IL-10 and TGFβ secretion from DCs, which drives Treg differentiation. TLR5 depletion or TSLP neutralization abrogates the protective effect of R. intestinalis on experimental colitis. TLR5-siRNA in Caco-2 cells, Tlr5-/- mice, bone marrow chimera mice, anti-TSLP/anti-TGFβ neutralizing antibodies, DC-T cell co-culture differentiation assays EBioMedicine High 36182776
2023 Clostridia flagella (TLR5 ligand) signal through TLR5/MyD88 on CD11c+ antigen-presenting cells to induce IL-22 secretion from ileal explants, which contributes to barrier protection against food allergy. This TLR5/MyD88 pathway works together with AhR signaling in RORγt+ cells to maintain intestinal barrier integrity. TLR5-KO, MyD88-KO, CD11c-specific MyD88-KO, and AhR-KO mice; ileal explant IL-22 assay; intestinal permeability measurement; anaphylaxis model Cell reports High 37742185
2004 TLR5 in the gastric epithelium undergoes dynamic relocalization from apical+basolateral to exclusively basolateral distribution during H. pylori infection, as determined by confocal microscopy in patient biopsies, suggesting infection-regulated polarized TLR5 localization modulates mucosal immune responses. Confocal immunofluorescence microscopy on human gastric biopsies from H. pylori gastritis patients vs. noninflamed controls Clinical and experimental immunology Medium 15147355

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.) 456 22344444
2014 TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination. Immunity 424 25220212
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2004 Expression and subcellular distribution of toll-like receptors TLR4, TLR5 and TLR9 on the gastric epithelium in Helicobacter pylori infection. Clinical and experimental immunology 192 15147355
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.) 182 25395539
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2011 Age-associated elevation in TLR5 leads to increased inflammatory responses in the elderly. Aging cell 129 22023165
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
2017 A conserved TLR5 binding and activation hot spot on flagellin. Scientific reports 125 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) 123 20826748
2016 HMGB1 Activates Proinflammatory Signaling via TLR5 Leading to Allodynia. Cell reports 119 27760316
2004 Activation of TLR3 and TLR5 in channel catfish exposed to virulent Edwardsiella ictaluri. Developmental and comparative immunology 111 15854683
2012 Luteolin downregulates TLR4, TLR5, NF-κB and p-p38MAPK expression, upregulates the p-ERK expression, and protects rat brains against focal ischemia. Brain research 110 22377454
2010 TLR5 or NLRC4 is necessary and sufficient for promotion of humoral immunity by flagellin. European journal of immunology 110 21072873
2005 Flagellin/TLR5 responses in epithelia reveal intertwined activation of inflammatory and apoptotic pathways. American journal of physiology. Gastrointestinal and liver physiology 110 16179598
2022 M1 macrophage-derived exosomes and their key molecule lncRNA HOTTIP suppress head and neck squamous cell carcinoma progression by upregulating the TLR5/NF-κB pathway. Cell death & disease 103 35210436
2007 Functional characterization of chicken TLR5 reveals species-specific recognition of flagellin. Molecular immunology 102 17964652
2010 Polymorphisms in the TLR4 and TLR5 gene are significantly associated with inflammatory bowel disease in German shepherd dogs. PloS one 96 21203467
2011 Inductive expression of toll-like receptor 5 (TLR5) and associated downstream signaling molecules following ligand exposure and bacterial infection in the Indian major carp, mrigal (Cirrhinus mrigala). Fish & shellfish immunology 95 22085689
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) 89 34507948
2022 Roseburia intestinalis stimulates TLR5-dependent intestinal immunity against Crohn's disease. EBioMedicine 79 36182776
2010 TLR5 functions as an endocytic receptor to enhance flagellin-specific adaptive immunity. European journal of immunology 75 21182074
2009 Immune responses of TLR5(+) lamina propria dendritic cells in enterobacterial infection. Journal of gastroenterology 72 19547909
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
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 62 24417966
2014 Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice. Cellular & molecular immunology 62 25418468
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
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) 58 24442437
2013 Airway structural cells regulate TLR5-mediated mucosal adjuvant activity. Mucosal immunology 58 24064672
2014 Ligation of TLR5 promotes myeloid cell infiltration and differentiation into mature osteoclasts in rheumatoid arthritis and experimental arthritis. Journal of immunology (Baltimore, Md. : 1950) 56 25200955
2012 Clostridium difficile flagellin stimulates toll-like receptor 5, and toxin B promotes flagellin-induced chemokine production via TLR5. Life sciences 56 23261530
2006 AsialoGM1 and TLR5 cooperate in flagellin-induced nucleotide signaling to activate Erk1/2. American journal of respiratory cell and molecular biology 56 16439799
2013 Functional TLR5 genetic variants affect human colorectal cancer survival. Cancer research 52 24154872
2008 Stimulation by TLR5 modulates osteoclast differentiation through STAT1/IFN-beta. Journal of immunology (Baltimore, Md. : 1950) 51 18209032
2018 TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer's disease. The Journal of experimental medicine 50 30158114
2022 Roseburia intestinalis and Its Metabolite Butyrate Inhibit Colitis and Upregulate TLR5 through the SP3 Signaling Pathway. Nutrients 47 35893896
2020 Gut Microbiota-Associated Activation of TLR5 Induces Apolipoprotein A1 Production in the Liver. Circulation research 46 32820707
2018 Emodin ameliorates ulcerative colitis by the flagellin-TLR5 dependent pathway in mice. International immunopharmacology 45 29669309
2010 Fusion protein of TLR5-ligand and allergen potentiates activation and IL-10 secretion in murine myeloid DC. Molecular immunology 43 20965571
2018 Duplicated TLR5 of zebrafish functions as a heterodimeric receptor. Proceedings of the National Academy of Sciences of the United States of America 42 29555749
2014 Mapping of TLR5 and TLR7 in central and distal human airways and identification of reduced TLR expression in severe asthma. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 42 24447081
2013 Impaired TLR5 functionality is associated with survival in melioidosis. Journal of immunology (Baltimore, Md. : 1950) 42 23447684
2012 TLR5 risk-associated haplotype for canine inflammatory bowel disease confers hyper-responsiveness to flagellin. PloS one 42 22279566
2007 Protein kinase D interaction with TLR5 is required for inflammatory signaling in response to bacterial flagellin. Journal of immunology (Baltimore, Md. : 1950) 42 17442957
2007 Blocking of the TLR5 activation domain hampers protective potential of flagellin DNA vaccine. Journal of immunology (Baltimore, Md. : 1950) 41 17617608
2015 TLR5, a novel mediator of innate immunity-induced osteoclastogenesis and bone loss. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 40 26207027
2012 PRAT4A-dependent expression of cell surface TLR5 on neutrophils, classical monocytes and dendritic cells. International immunology 40 22836022
2016 TLR5 mediates CD172α(+) intestinal lamina propria dendritic cell induction of Th17 cells. Scientific reports 39 26907705
2017 Treponema pallidum flagellins stimulate MMP-9 and MMP-13 expression via TLR5 and MAPK/NF-κB signaling pathways in human epidermal keratinocytes. Experimental cell research 37 28982539
2016 MicroRNA-induced negative regulation of TLR-5 in grass carp, Ctenopharyngodon idella. Scientific reports 36 26727169
2017 Relevant genetic polymorphisms and kidney expression of Toll-like receptor (TLR)-5 and TLR-9 in lupus nephritis. Clinical and experimental immunology 35 28763101
2023 TLR5 Signaling in the Regulation of Intestinal Mucosal Immunity. Journal of inflammation research 34 37337514
2009 Decreased Toll-like receptor-5 (TLR-5) expression in the mucosa of ulcerative colitis patients. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 34 20083854
2016 Clostridium difficile flagella predominantly activate TLR5-linked NF-κB pathway in epithelial cells. Anaerobe 33 26790921
2015 Activation of NLRC4 downregulates TLR5-mediated antibody immune responses against flagellin. Cellular & molecular immunology 33 25914934
2006 Characterization and functional investigation of single nucleotide polymorphisms (SNPs) in the human TLR5 gene. Human mutation 33 16470719
2015 Flagellin-dependent TLR5/caveolin-1 as a promising immune activator in immunosenescence. Aging cell 32 26223660
2015 Pyrimidine Triazole Thioether Derivatives as Toll-Like Receptor 5 (TLR5)/Flagellin Complex Inhibitors. ChemMedChem 32 26634412
2022 Cyprinid-specific duplicated membrane TLR5 senses dsRNA as functional homodimeric receptors. EMBO reports 31 35678424
2017 Identification, characterization and expression analysis of TLR5 in the mucosal tissues of turbot (Scophthalmus maximus L.) following bacterial challenge. Fish & shellfish immunology 31 28705722
2016 Physiological TLR5 expression in the intestine is regulated by differential DNA binding of Sp1/Sp3 through simultaneous Sp1 dephosphorylation and Sp3 phosphorylation by two different PKC isoforms. Nucleic acids research 30 27060138
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2015 TLR5 Ligand-Secreting T Cells Reshape the Tumor Microenvironment and Enhance Antitumor Activity. Cancer research 30 25795705
2013 The effects of oral and enteric Campylobacter concisus strains on expression of TLR4, MD-2, TLR2, TLR5 and COX-2 in HT-29 cells. PloS one 29 23437263
2012 Airway epithelial expression of TLR5 is downregulated in healthy smokers and smokers with chronic obstructive pulmonary disease. Journal of immunology (Baltimore, Md. : 1950) 29 22855713
2019 Dysregulation of TLR5 and TAM Ligands in the Alzheimer's Brain as Contributors to Disease Progression. Molecular neurobiology 28 30852796
2017 TLR2, TLR3 and TLR5 regulation of pro-inflammatory and pro-labour mediators in human primary myometrial cells. Journal of reproductive immunology 28 28844021
2017 Host species adaptation of TLR5 signalling and flagellin recognition. Scientific reports 28 29247203
2010 TRIF modulates TLR5-dependent responses by inducing proteolytic degradation of TLR5. The Journal of biological chemistry 28 20452988
2014 MAP1S controls breast cancer cell TLR5 signaling pathway and promotes TLR5 signaling-based tumor suppression. PloS one 27 24466264
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2014 Redundant and cooperative interactions between TLR5 and NLRC4 in protective lung mucosal immunity against Pseudomonas aeruginosa. Journal of innate immunity 26 25402425
2018 Characterization of TLR5 and TLR9 from silver pomfret (Pampus argenteus) and expression profiling in response to bacterial components. Fish & shellfish immunology 25 29890218
2017 Treponema pallidum flagellins elicit proinflammatory cytokines from human monocytes via TLR5 signaling pathway. Immunobiology 25 28126263
2020 Convergent Losses of TLR5 Suggest Altered Extracellular Flagellin Detection in Four Mammalian Lineages. Molecular biology and evolution 24 32145026
2020 SP1 activated-lncRNA SNHG1 mediates the development of epilepsy via miR-154-5p/TLR5 axis. Epilepsy research 24 33096314
2017 TLR5/7-mediated PI3K activation triggers epithelial-mesenchymal transition of ovarian cancer cells through WAVE3-dependent mesothelin or OCT4/SOX2 expression. Oncology reports 24 28901470
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2015 Common and specific downstream signaling targets controlled by Tlr2 and Tlr5 innate immune signaling in zebrafish. BMC genomics 23 26208853
2012 A TLR5 agonist enhances CD8(+) T cell-mediated graft-versus-tumor effect without exacerbating graft-versus-host disease. Journal of immunology (Baltimore, Md. : 1950) 23 23045613
2008 IL-1beta expression in Int407 is induced by flagellin of Vibrio cholerae through TLR5 mediated pathway. Microbial pathogenesis 23 18314303
2017 Studies on expression pattern of toll-like receptor 5 (TLR5) in Edwardsiella tarda infected Pangasianodon hypophthalmus. Fish & shellfish immunology 22 28159691
2020 Escape of TLR5 Recognition by Leptospira spp.: A Rationale for Atypical Endoflagella. Frontiers in immunology 21 32849665
2013 Crosstalk between TLR5 and Notch1 signaling in epithelial cells during intestinal inflammation. International journal of molecular medicine 21 24048326
2023 Commensal bacteria signal through TLR5 and AhR to improve barrier integrity and prevent allergic responses to food. Cell reports 20 37742185
2022 TLR5 recognizes Aeromonas hydrophila flagellin and interacts with MyD88 in Nile tilapia. Developmental and comparative immunology 20 35405183
2018 Nucleoside Diphosphate Kinase-3 (NME3) Enhances TLR5-Induced NFκB Activation. Molecular cancer research : MCR 20 29523766
2015 Common TLR5 mutations control cancer progression. Cancer cell 20 25584886
2013 Immunohistochemical detection of Helicobacter pylori without association of TLR5 expression in oral squamous cell carcinoma. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 20 23659788
2011 All-trans retinoic acid induces TLR-5 expression and cell differentiation and promotes flagellin-mediated cell functions in human THP-1 cells. Immunology letters 20 21237205
2017 Leukocyte TLR5 deficiency inhibits atherosclerosis by reduced macrophage recruitment and defective T-cell responsiveness. Scientific reports 19 28202909

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