Affinage

TLR9

Toll-like receptor 9 · UniProt Q9NR96

Length
1032 aa
Mass
115.9 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 30 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

TLR9 is an intracellular nucleic-acid pattern-recognition receptor that surveys endolysosomal compartments for DNA and initiates innate immune signaling, but its biology extends to metabolic and neuronal functions beyond immunity (PMID:15588423, PMID:32051584, PMID:38538785). At rest TLR9 resides in the endoplasmic reticulum and translocates to a tubular lysosomal compartment upon CpG-DNA encounter, where it binds ligand and signals (PMID:15588423). Activation universally requires proteolytic cleavage in endolysosomes, with the cathepsin requirement differing by cell type—cathepsins L and S jointly in macrophages versus cathepsin L alone in B cells—and is tightly coupled to UNC93B1 expression (PMID:23241879). Compartment-specific trafficking dictates signaling output: HRS mediates ubiquitin-dependent endolysosomal targeting (PMID:22423970), BAD-LAMP (LAMP5) sorts TLR9 between late-endosomal NF-κB-driving and VAMP3+ IFN-driving compartments (PMID:29030552), the tetraspanin CD82 chaperones TLR9 from the ER and enables myddosome formation (PMID:31408613), and a DHHC3/PPT1 S-palmitoylation cycle at C258/C265 controls Golgi-to-endosome trafficking and release from UNC93B1 (PMID:38169466). Within lysosomes, DNase II processes CpG-A and bacterial genomic DNA into short fragments that constitute the activating ligands (PMID:25600358), and TLR9 recognizes diverse DNA species including RNA:DNA hybrids and oxidized/mitochondrial DNA (PMID:24514026, PMID:29880709, PMID:36835307). Upon activation TLR9 assembles a MyD88–IRAK–TRAF6 complex that recruits PKD1 to drive NF-κB and MAPK activation (PMID:18641342), with MAL and BTK serving as additional required cofactors for cytokine and type I IFN induction (PMID:24612681, PMID:31851971). Structure-function dissection in vivo reveals that TLR9 operates through three distinct modes—a ligand- and MyD88-independent scaffold function, ligand-dependent MyD88-independent regulatory signaling, and MyD88-dependent proinflammatory signaling—and B cell-intrinsic TLR9 is protective in lupus, restraining pathogenic plasmablast and age-associated B cell differentiation (PMID:36151396, PMID:32191633). Independent of immunity, TLR9 interacts with beclin 1 to regulate PI3KC3-C2 assembly and AMPK-dependent glucose uptake in exercising skeletal muscle (PMID:32051584), and supports centrosomal DNA-damage repair in hippocampal neurons during memory formation (PMID:38538785).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2004 Medium

    Establishing where TLR9 senses its ligand resolved why it detects intracellular rather than surface DNA, defining it as a compartmentalized receptor distinct from cell-surface TLRs.

    Evidence Fluorescent-tagged TLR9/TLR4 localization and CpG-DNA trafficking in human pDCs

    PMID:15588423

    Open questions at the time
    • Did not define the molecular machinery driving ER-to-lysosome translocation
    • Did not address why endosomal localization is required for ligand discrimination
  2. 2005 Medium

    Identifying CD32 as a delivery receptor explained how extracellular DNA-immune complexes reach the intracellular TLR9 compartment, linking TLR9 to autoimmune activation.

    Evidence Subcellular colocalization and functional stimulation of CD32+ vs CD32- pDCs with SLE immune complexes

    PMID:15668740

    Open questions at the time
    • Did not establish direct physical interaction between CD32 and TLR9
    • Did not define the handoff step from CD32 to TLR9 within the lysosome
  3. 2005 High

    Demonstrating that CpG-DNA can activate Akt independently of TLR9 via DNA-PKcs distinguished TLR9-dependent from TLR9-independent DNA sensing branches.

    Evidence In vitro kinase assay with purified DNA-PK, TLR9-/- and DNA-PKcs-/- macrophages, and Co-IP

    PMID:15678105

    Open questions at the time
    • Did not address whether the two DNA-sensing branches cross-regulate
    • Scope limited to Akt activation
  4. 2008 Medium

    Placing PKD1 within the TLR9/MyD88/IRAK/TRAF6 complex identified a kinase node required to propagate signaling to NF-κB and MAPKs.

    Evidence Co-IP, siRNA knockdown, and kinase activation assays in macrophages

    PMID:18641342

    Open questions at the time
    • Direct PKD1 substrates in the pathway not defined
    • Single cell type
  5. 2012 Medium

    Defining HRS-dependent ubiquitin-driven endolysosomal targeting and uncovering broad cofactor networks mapped the trafficking requirements for TLR9 signaling.

    Evidence Genome-wide RNAi screen with functional validation of HRS knockdown on TLR9 trafficking

    PMID:22423970

    Open questions at the time
    • The ubiquitin ligase acting on TLR9 not identified
    • Most screen hits not individually mechanistically validated
  6. 2012 High

    Showing that proteolytic cleavage is universally required but cell-type-dependent in its cathepsin usage established processing as an obligatory activation step and explained cell-type differences in TLR9 responsiveness.

    Evidence Transgenic TLR9-GFP mice, cathepsin inhibitors, and UNC93B1 mutant mice across macrophages, DCs, and B cells

    PMID:23241879

    Open questions at the time
    • Structural basis of the cleaved active receptor not resolved
    • Mechanism coupling UNC93B1 level to cleavage rate not defined
  7. 2014 Medium

    Identifying RNA:DNA hybrids as TLR9 ligands and demonstrating BTK as a required kinase broadened the ligand repertoire and the kinase requirements for TLR9-driven cytokine output.

    Evidence MyD88-deficient DCs with viral RNA:DNA hybrids; XLA patient DCs and ibrutinib inhibition

    PMID:24514026 PMID:24612681

    Open questions at the time
    • Direct hybrid binding to TLR9 not structurally shown
    • BTK's precise position in the TLR9 signalosome not defined
  8. 2015 High

    Establishing that DNase II generates the short DNA fragments that actually activate TLR9 redefined the true ligand as a processed product rather than the input oligonucleotide.

    Evidence DNase II-deficient DCs, enzymatically inactive mutants, synthetic fragment rescue, and colocalization

    PMID:25600358

    Open questions at the time
    • Why CpG-B bypasses the DNase II requirement not fully explained
    • Structural basis of fragment recognition not resolved
  9. 2016 Medium

    Linking Dectin-1-driven phagosomal trafficking and identifying mtDNA-microparticle ligands extended TLR9 sensing to fungal and metabolic-disease contexts.

    Evidence Live-cell imaging with Syk inhibitors (Dectin-1); cell-type-specific TLR9 knockout and microparticle depletion in NASH

    PMID:26808498 PMID:26829985

    Open questions at the time
    • How phagosomal vs endosomal TLR9 pools differ functionally not defined
    • Mechanism of mtDNA escape into microparticles not detailed
  10. 2017 High

    Demonstrating that BAD-LAMP sorts TLR9 between distinct endolysosomal compartments explained how a single receptor produces either NF-κB/TNF or type I IFN outputs.

    Evidence siRNA silencing of BAD-LAMP in primary human pDCs with multi-marker compartment imaging and cytokine readout

    PMID:29030552

    Open questions at the time
    • How compartment identity is mechanistically converted into distinct signaling not fully defined
    • Restricted to pDCs
  11. 2018 Medium

    Showing that mitochondrial DNA release (during RNA-virus infection or Opa1 loss) activates TLR9 established mtDNA as an endogenous danger ligand driving sterile and antiviral inflammation.

    Evidence TLR9 knockout/knockdown DCs with DENV; muscle-specific Opa1 knockout with TLR9 blockade and mtDNA depletion

    PMID:29632021 PMID:29880709

    Open questions at the time
    • How cytosolic mtDNA reaches endolysosomal TLR9 not defined
    • Relative contribution of TLR9 vs cGAS context-dependent
  12. 2019 Medium

    Identifying CD82, MAL, and Cav-1 as context-specific cofactors refined the trafficking and adapter requirements for myddosome formation and IRF-directed signaling.

    Evidence Co-IP and knockout for CD82 (macrophages) and Cav-1 (neutrophils); MAL-deficient macrophages with ERK inhibition

    PMID:31408613 PMID:31534550 PMID:31851971

    Open questions at the time
    • Whether these cofactors act in the same or distinct cell contexts not reconciled
    • Direct binding interfaces not mapped
  13. 2020 High

    Discovering the TLR9-beclin 1 interaction in skeletal muscle revealed a non-immune metabolic function controlling exercise-induced AMPK activation and glucose uptake.

    Evidence TLR9 knockout mice, Co-IP with beclin 1, ex vivo muscle contraction, and beclin1/UVRAG/BCL2 genetic models

    PMID:32051584

    Open questions at the time
    • Whether this requires DNA ligand or signaling is unresolved
    • How TLR9 senses energy stress not defined
  14. 2020 High

    Cell-type-specific genetics showed B cell-intrinsic TLR9 is protective in lupus, overturning the assumption that TLR9 is uniformly pathogenic in autoimmunity.

    Evidence Cell-type-specific TLR9 deletion and overexpression in lupus-prone mice with nephritis and autoantibody phenotyping

    PMID:32191633

    Open questions at the time
    • Molecular basis of the B cell-protective function not defined at this stage
    • How protective and pathogenic roles are balanced unclear
  15. 2022 High

    Structure-function point mutants dissected TLR9 into ligand-independent scaffold, ligand-dependent MyD88-independent regulatory, and MyD88-dependent proinflammatory modes, mechanistically explaining its protective B-cell function.

    Evidence TLR9K51E and TLR9P915H point mutants and triple-mixed bone marrow chimeras in MRL/lpr mice

    PMID:36151396

    Open questions at the time
    • Molecular effectors of the MyD88-independent scaffold function not identified
    • How the three modes are partitioned across cell states unclear
  16. 2024 Medium

    Defining a DHHC3/PPT1 palmitoylation cycle and an m6A/METTL3/YTHDF1 expression circuit added post-translational and post-transcriptional layers controlling TLR9 trafficking and abundance.

    Evidence Mass spectrometry, palmitoylation-site mutagenesis, DHHC3/PPT1 manipulation, and lupus models; m6A analysis with METTL3/YTHDF1 perturbation

    PMID:38169466 PMID:38537697

    Open questions at the time
    • How palmitoylation state couples to specific signaling outputs not fully mapped
    • Whether EBV-driven TLR9 suppression generalizes beyond B cells unclear
  17. 2024 Medium

    Identifying a neuronal role for TLR9 in centrosomal DNA-damage repair during memory formation extended its function entirely outside innate immunity.

    Evidence Neuron-specific Tlr9 knockdown, fear conditioning, CA1 transcriptomics, and immunofluorescence of centrosomal repair complexes

    PMID:38538785

    Open questions at the time
    • Whether this requires canonical DNA ligand sensing not defined
    • Mechanism linking TLR9 to centrosome and ciliogenesis function unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TLR9's distinct conformational/signaling states (scaffold vs MyD88-dependent vs IRF-driven) are structurally encoded and selected within specific subcellular compartments remains unresolved.
  • No structural model of the active cleaved receptor in distinct compartments
  • Mechanism converting compartment identity into signaling outcome not defined
  • Unifying principle connecting immune, metabolic, and neuronal functions absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 3 GO:0060089 molecular transducer activity 3 GO:0140299 molecular sensor activity 3
Localization
GO:0005764 lysosome 4 GO:0005768 endosome 3 GO:0005783 endoplasmic reticulum 3 GO:0005886 plasma membrane 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-1430728 Metabolism 1
Partners
BAD-LAMPBECLIN 1CAV-1CD82DHHC3MYD88PKD1UNC93B1
Complex memberships
PI3KC3-C2 (beclin 1/UVRAG)myddosome (MyD88-IRAK-TRAF6)

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 DNA-containing immune complexes from SLE serum activate plasmacytoid DCs via cooperative interaction between CD32 (FcγRIIa) and TLR9: CD32 delivers SLE-ICs to intracellular lysosomes containing TLR9, where signaling is initiated. SLE-ICs transiently colocalized to a subcellular compartment containing both CD32 and TLR9, and only CD32+ PDCs internalized and responded to SLE-ICs. Subcellular colocalization imaging, functional cell stimulation with CD32+ vs CD32- PDCs, cytokine/chemokine readout The Journal of clinical investigation Medium 15668740
2004 TLR9 is expressed in the endoplasmic reticulum at rest and translocates to a tubular lysosomal compartment upon CpG-DNA stimulation, where it binds DNA and initiates signaling. In contrast, TLR4 is expressed on the plasma membrane. Fluorescent protein-tagged TLR9 and TLR4 subcellular localization comparison; fluorescently tagged CpG-DNA trafficking in human pDCs Journal of endotoxin research Medium 15588423
2008 Protein kinase D1 (PKD1) is activated by CpG-B DNA through a pathway dependent on endosomal pH, TLR9, MyD88, and IRAK1 in macrophages. Upon CpG-B stimulation, PKD1 interacts with the TLR9/MyD88/IRAK/TRAF6 signaling complex, and knockdown of PKD1 impairs NF-κB and MAPK activation and downstream cytokine expression. Co-immunoprecipitation, siRNA knockdown, kinase activation assays in macrophages Journal of immunology Medium 18641342
2005 TLR9 is NOT required for CpG-DNA-induced Akt activation; instead, DNA-PKcs directly phosphorylates and activates Akt in response to CpG-DNA and associates with Akt upon stimulation in bone marrow-derived macrophages, triggering transient nuclear translocation of Akt. In vitro kinase assay with purified DNA-PK and recombinant Akt; bone marrow-derived macrophages from TLR9-/- and DNA-PKcs-/- mice; Co-IP of DNA-PKcs with Akt The EMBO journal High 15678105
2012 HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) is required for ubiquitin-dependent TLR9 targeting to the endolysosome, identified via genome-wide RNAi screening; cofactors including ubiquitin-protein ligase activities, sphingolipid metabolism, chromatin modifications, and ancient stress response pathways modulate TLR9 endosomal signaling. Genome-wide RNAi screen; integrative systems analysis; functional validation of HRS knockdown on TLR9 endolysosomal trafficking Cell host & microbe Medium 22423970
2012 TLR9 requires proteolytic cleavage for activation in all primary APC types tested (macrophages, dendritic cells, B cells), but the cathepsin requirement and rate of cleavage differ by cell type: macrophages require cathepsins L and S jointly, while B cells require cathepsin L alone. TLR9 trafficking and processing kinetics also differ between cell types, with B cells showing faster processing and near-exclusive endolysosomal localization at rest. UNC93B1 expression level is tightly correlated with TLR9-GFP cleavage. Transgenic TLR9-GFP mice; proteolytic processing assays; cathepsin inhibitors; UNC93B1 3d mutant mice; bone marrow-derived macrophages, DCs, and B cells Journal of immunology High 23241879
2015 DNase II digestion of DNA in endolysosomes is required for TLR9 activation by CpG-A (but not CpG-B). DNase II cleaves CpG-A from 20-mer to 11–12-mer fragments, and these 3′ 11-mer fragments can activate DNase II-deficient DCs. CpG-A shows higher colocalization with LAMP-2+ lysosomes than CpG-B, and DNase II localizes to LAMP-2+ lysosomes upon CpG-A stimulation. DNase II is also required for TLR9 activation by bacterial genomic DNA. DNase II-deficient dendritic cells; enzymatically inactive DNase II mutants; synthetic DNA fragment rescue experiments; subcellular colocalization microscopy Nature communications High 25600358
2017 BAD-LAMP (LAMP5) controls TLR9 trafficking to LAMP1+ late endosomes in human plasmacytoid dendritic cells, promoting NF-κB activation and TNF production. An inducible VAMP3+/LAMP2+/LAMP1- endolysosomal compartment exists in pDCs from which TLR9 activation triggers type I IFN expression. BAD-LAMP silencing enhances TLR9 retention in this IFN-producing compartment, whereas sustained BAD-LAMP expression promotes TLR9 sorting to late endosomes and limits type I IFN production. siRNA silencing of BAD-LAMP in primary human pDCs; subcellular compartment characterization by multi-marker imaging; cytokine output measurement Nature communications High 29030552
2016 Dectin-1 controls TLR9 trafficking to phagosomes containing β-1,3 glucan. β-1,3 glucan bead recognition by Dectin-1 induces dynamic redistribution and accumulation of cleaved TLR9 to phagosomes. This trafficking requires phagosomal acidification and Dectin-1-mediated spleen tyrosine kinase (Syk) activation. Dectin-1 also regulates TLR9-dependent gene expression. Live-cell imaging; pharmacological inhibition of phagosomal acidification; Syk inhibitors; Dectin-1-dependent trafficking assays with fungal pathogens Journal of immunology Medium 26829985
2019 The tetraspanin CD82 associates with TLR9 in the endoplasmic reticulum and post-ER compartments of macrophages, is essential for TLR9-dependent myddosome formation in response to CpG stimulation, and modulates TLR9-dependent NF-κB nuclear translocation and inflammatory cytokine production. Co-immunoprecipitation; myddosome formation assay; NF-κB nuclear translocation assay; CD82-deficient macrophages FASEB journal Medium 31408613
2014 Bruton's tyrosine kinase (BTK) is required for human dendritic cell activation via TLR9: CpG/TLR9-induced upregulation of activation markers (CD86, CD83, CD80, HLA-DR) and cytokine production (IL-6, IL-12, TNF-α, IL-10) are completely impaired in XLA patients lacking functional BTK, and BTK mediates TLR9-dependent STAT1/3 upregulation. BTK inhibition with ibrutinib phenocopies XLA in healthy DCs. Human DCs from XLA patients; ibrutinib pharmacological inhibition; cytokine ELISA; flow cytometry for activation markers; STAT1/3 western blotting The Journal of allergy and clinical immunology Medium 24612681
2014 RNA:DNA hybrids are a novel molecular pattern specifically sensed by TLR9. Hybrid-induced pro-inflammatory cytokine and type I IFN production in dendritic cells requires MyD88-dependent signaling, demonstrating TLR9 as the sensor. Cytokine induction in dendritic cells with viral-derived RNA:DNA hybrids; MyD88-deficient cells; TLR9-specific pathway analysis The EMBO journal Medium 24514026
2024 TLR9 undergoes a cycle of S-palmitoylation and depalmitoylation that controls its signaling. DHHC3 (protein acyltransferase) palmitoylates TLR9 at C258 and C265 in the Golgi and regulates TLR9 trafficking to endosomes. PPT1 (palmitoyl-protein thioesterase 1) removes S-palmitoylation from TLR9 in lysosomes and facilitates TLR9 release from UNC93B1. PPT1 deficiency or inhibition reduces TLR9-dependent IFNα and TNF production. Mass spectrometry for palmitoylation site identification; biochemical palmitoylation assays; DHHC3 and PPT1 genetic/chemical manipulation; TLR9 trafficking assays; murine lupus model (B6.Sle1yaa); ex vivo human pDC experiments Nature communications High 38169466
2022 TLR9 possesses distinct signaling modes: (1) a ligand- and MyD88-independent 'scaffold' protective function; (2) ligand-dependent but MyD88-independent regulatory signaling; and (3) MyD88-mediated proinflammatory signaling. The MyD88-independent regulatory roles are B cell-intrinsic and restrain differentiation into pathogenic age-associated B cells and plasmablasts in lupus. Two TLR9 point mutants generated in lupus-prone MRL/lpr mice (TLR9K51E lacking ligand binding; TLR9P915H lacking MyD88 binding); triple-mixed bone marrow chimeras; disease phenotyping Nature immunology High 36151396
2020 TLR9 interacts with beclin 1 and this interaction increases during energy stress (glucose starvation, endurance exercise). TLR9 regulates assembly of the endolysosomal PI3KC3-C2 complex (containing beclin 1 and UVRAG) in skeletal muscle during exercise. TLR9-deficient mice fail to activate AMPK in skeletal muscle during exercise and show reduced GLUT4 plasma membrane localization, but autophagy is not impaired. TLR9 functions cell-autonomously in ex vivo contraction-induced AMPK activation and glucose uptake. TLR9-knockout mice; Co-IP of TLR9 with beclin 1; ex vivo skeletal muscle contraction; AMPK activation assays; GLUT4 localization; beclin 1 and UVRAG conditional knockouts; BCL2 mutant mice Nature High 32051584
2019 During inflammatory preconditioning in neutrophils, TLR9 undergoes membrane translocation from the cytosol to the plasma membrane, where it binds to Cav-1. This TLR9-Cav-1 interaction enables TLR9 to facilitate MyD88-mediated TRAF3 and IRF3 signal transduction. Depletion of either TLR9 or Cav-1 eliminates the protective effect. Co-IP; fluorescence microscopy; FRET; flow cytometry; TLR9 and Cav-1 knockout models; sepsis models in vitro and in vivo Theranostics Medium 31534550
2019 MAL (MyD88 adapter-like) adapter protein is engaged in TLR9-dependent IFNβ and TNFα expression in macrophages infected with HSV-1 or treated with CpG-C, acting through a non-canonical NF-κB pathway. ERK1/2 kinases are required for TLR9-dependent IFNβ and TNFα induction via this pathway. MAL-deficient macrophages; ERK1/2 inhibitor; HSV-1 infection and CpG-C stimulation; cytokine measurement; NF-κB pathway analysis Journal of innate immunity Medium 31851971
2018 Dengue virus (an RNA virus) activates TLR9 in human dendritic cells by inducing release of mitochondrial DNA (mtDNA) into the cytosol. DENV infection disrupts TFAM-mtDNA association and activates mitochondrial permeability transition pores to release mtDNA; this activates TLR9 signaling leading to IFN production. TLR9 and cGAS comparably contribute to DENV-induced immune activation. TLR9 siRNA knockdown; TLR9-knockout bone marrow-derived DCs; side-by-side comparison with cGAS knockdown; mtDNA release assays; IFN measurement EMBO reports Medium 29880709
2018 Opa1 deficiency in muscle causes mitochondrial DNA release, which activates TLR9, leading to NF-κB activation and inflammation. Blockage or repression of TLR9 prevents NF-κB activation and inflammation in Opa1-deficient muscle cells, demonstrating TLR9 as the mediator upstream of NF-κB in this pathway. This process is cell-autonomous and independent of cell death. Muscle-specific Opa1 knockout mice; TLR9 knockdown/blockade; mtDNA depletion; NF-κB reporter assays; inflammatory gene expression The EMBO journal Medium 29632021
2012 TLR9-induced type I IFN mediates anti-inflammatory effects in experimental colitis. TLR9 or MyD88 deficiency abolishes the protective effect of probiotics and probiotic DNA. Neutralizing type I IFN antibodies abrogate TLR9-mediated anti-inflammatory effects, while recombinant IFN-β mimics them. TLR9-/- and MyD88-/- mice; anti-IFN neutralizing antibodies; recombinant IFN-β administration; DSS colitis model Annals of the New York Academy of Sciences Medium 17057215
2016 Hepatocyte-derived mitochondrial DNA (mtDNA) in microparticles activates TLR9 in NASH. NASH development in response to high-fat diet requires TLR9 on lysozyme-expressing cells. Removal of mtDNA-containing microparticles from plasma substantially reduces TLR9 activation capacity. TLR9 conditional knockout on lysozyme+ cells; microparticle depletion from plasma; TLR9 activation assays with NASH patient plasma; TLR9 antagonist treatment The Journal of clinical investigation High 26808498
2012 TLR9-dependent signaling in pneumococcal pneumonia induces KLF4 expression via a bacterial DNA-TLR9-MyD88-Src kinase pathway. KLF4 is recruited to the IL-10 promoter and is required for IL-10 expression during pneumococcal infection; siRNA knockdown of KLF4 blocks IL-10 induction. siRNA knockdown; chromatin immunoprecipitation; Western blot; ELISA; TLR9/MyD88 pathway inhibition; murine pneumonia model The European respiratory journal Medium 22653776
2024 TLR9 signaling plays a role in memory formation: hippocampal CA1 neurons with learning-induced double-stranded DNA breaks and nuclear envelope ruptures activate TLR9 signaling and accumulate centrosomal DNA damage repair complexes. Neuron-specific TLR9 knockdown impairs memory while blunting fear conditioning-induced gene expression changes in CA1 neuron clusters. TLR9 has an essential role in centrosome function, DNA damage repair, ciliogenesis, and perineuronal net formation. Neuron-specific Tlr9 knockdown; contextual fear conditioning; transcriptomic analysis of CA1 clusters; immunofluorescence for centrosomal complexes and DNA damage markers Nature Medium 38538785
2024 EBV suppresses TLR9 expression by downregulating m6A modification of TLR9 mRNA. EBV nuclear antigen 1 (EBNA1) promotes K48-linked ubiquitin-proteasome degradation of METTL3 (m6A writer), reducing TLR9 mRNA stability. YTHDF1 acts as an m6A reader of TLR9 mRNA, enhancing TLR9 expression by promoting translation in an m6A-dependent manner. m6A modification analysis; METTL3 knockdown; YTHDF1 functional studies; ubiquitin-proteasome pathway assays; METTL3 inhibitor (STM2457); B cell proliferation and immunoglobulin assays The Journal of biological chemistry Medium 38537697
2023 Oxidized mitochondrial DNA (ox-mtDNA) activates the TLR9-MyD88-inflammasome pathway in MDS hematopoietic stem and progenitor cells, demonstrated by increased lysosome formation, IRF7 translocation, ISG production, and TLR9 redistribution to the cell surface. TLR9 is necessary for ox-mtDNA-mediated NLRP3 inflammasome activation, shown by chemical inhibition and CRISPR knockout; TLR9 overexpression sensitizes cells to ox-mtDNA. TLR9 inhibition restores hematopoietic colony formation. CRISPR knockout; TLR9 lentiviral overexpression; TLR9 chemical inhibition; IRF7 translocation assay; inflammasome activation assays; colony formation assay International journal of molecular sciences Medium 36835307
2011 TLR9 and P2X7 are DAMP receptors upstream of NLRP3 inflammasome activation in acute pancreatitis. Genetic deletion of Tlr9 reduces pancreatic edema, inflammation, and pro-IL-1β expression. TLR9 is expressed in resident immune cells (predominantly macrophages) of the pancreas. Tlr9-/- mice; caerulein-induced pancreatitis; TLR9 antagonist IRS954; pro-IL-1β expression; histopathology Gastroenterology Medium 21439959
2020 B cell-intrinsic TLR9 expression is protective in lupus: TLR9 deficiency specifically in B cells exacerbates nephritis while extinguishing anti-nucleosome antibodies. B cell-specific TLR9 overexpression ameliorates nephritis. TLR9 deficiency in dendritic cells, plasmacytoid DCs, and neutrophils had no discernible effect on disease. Cell-type-specific TLR9 deletion and overexpression alleles in lupus-prone mice; nephritis histopathology; autoantibody measurement The Journal of clinical investigation High 32191633
2015 TLR9 ligation in pancreatic stellate cells (PSCs) induces fibrogenic transformation and secretion of CCL11, which promotes epithelial cell proliferation. TLR9 also has immune-suppressive effects in the pancreatic tumor microenvironment via induction of regulatory T cell recruitment and MDSC proliferation. TLR9 deletion mice; TLR9 ligation in isolated PSCs; CCL11 measurement; epithelial proliferation assays; immune cell characterization in tumor microenvironment The Journal of experimental medicine Medium 26481685
2013 FCRL3 augments TLR9-mediated B cell proliferation, activation, and survival, but abrogates plasma cell differentiation and antibody production by halting BLIMP1 induction in an ERK-dependent fashion. FCRL3 ligation amplifies NF-κB and MAPK signaling cascades downstream of TLR9. FCRL3 ligation combined with CpG ODN (TLR9 agonist) in human B cells; NF-κB and MAPK signaling assays; BLIMP1 expression; ERK inhibition European journal of immunology Medium 23857366
2022 Pro-inflammatory PS-ASOs require TLR9 signaling, but their innate immune activity does not correlate with TLR9 binding affinity, suggesting alternative PS-ASO binding sites on TLR9 leading to full, partial, or no activation. Extracellular proteins HMGB1, S100A8, and HRG enhance innate immune responses of PS-ASOs, suggesting PS-ASO-protein complexes are sensed by TLR9. Reducing PS content of PS-ASOs decreases innate immune responses. TLR9 binding affinity measurements; co-incubation competition assays; recombinant protein enhancement assays; PS content modulation Nucleic acids research Low 35848907

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. The Journal of clinical investigation 667 15668740
2009 Immunotherapeutic applications of CpG oligodeoxynucleotide TLR9 agonists. Advanced drug delivery reviews 458 19211030
2016 Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. The Journal of clinical investigation 403 26808498
2007 Development of TLR9 agonists for cancer therapy. The Journal of clinical investigation 349 17476348
2008 TLR9 as a key receptor for the recognition of DNA. Advanced drug delivery reviews 325 18262306
2008 Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene 319 18176597
2011 TLR9 and the NLRP3 inflammasome link acinar cell death with inflammation in acute pancreatitis. Gastroenterology 242 21439959
2010 Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis. BMC cancer 194 21129170
2024 Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice. Nature communications 175 38169466
2014 Mitochondrial DNA induces inflammation and increases TLR9/NF-κB expression in lung tissue. International journal of molecular medicine 175 24535292
2018 Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency. The EMBO journal 170 29632021
2012 TLR7 and TLR9 in SLE: when sensing self goes wrong. Immunologic research 164 22434514
2002 Interactions between bacterial CpG-DNA and TLR9 bridge innate and adaptive immunity. Current opinion in microbiology 164 11834371
2015 TLR9 ligation in pancreatic stellate cells promotes tumorigenesis. The Journal of experimental medicine 147 26481685
2016 The Role of TLR2, TLR4, and TLR9 in the Pathogenesis of Atherosclerosis. International journal of inflammation 144 27795867
2014 RNA:DNA hybrids are a novel molecular pattern sensed by TLR9. The EMBO journal 136 24514026
2011 Hepatitis B virus impairs TLR9 expression and function in plasmacytoid dendritic cells. PloS one 130 22046272
2015 DNase II-dependent DNA digestion is required for DNA sensing by TLR9. Nature communications 123 25600358
2010 Study of TLR3, TLR4, and TLR9 in prostate carcinomas and their association with biochemical recurrence. Cancer immunology, immunotherapy : CII 122 20978888
2015 TLR2 and TLR9 contribute to alcohol-mediated liver injury through induction of CXCL1 and neutrophil infiltration. American journal of physiology. Gastrointestinal and liver physiology 117 25930080
2019 Below the surface: The inner lives of TLR4 and TLR9. Journal of leukocyte biology 115 30900780
2011 Overexpression of TLR3, TLR4, TLR7 and TLR9 in esophageal squamous cell carcinoma. World journal of gastroenterology 108 21990957
2008 Comparison of human B cell activation by TLR7 and TLR9 agonists. BMC immunology 103 18652679
2013 Leukemia cell-targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity. Blood 93 24169824
2018 Infection with the dengue RNA virus activates TLR9 signaling in human dendritic cells. EMBO reports 92 29880709
2005 DNA-PKcs, but not TLR9, is required for activation of Akt by CpG-DNA. The EMBO journal 89 15678105
2003 Differential signaling by CpG DNA in DCs and B cells: not just TLR9. Trends in immunology 89 14552833
2010 Targeting the TLR9-MyD88 pathway in the regulation of adaptive immune responses. Expert opinion on therapeutic targets 87 20560798
2009 CpG oligodeoxynucleotides as TLR9 agonists: therapeutic applications in cancer. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy 86 19894778
2020 B cell-intrinsic TLR9 expression is protective in murine lupus. The Journal of clinical investigation 85 32191633
2006 TLR9 and the recognition of self and non-self nucleic acids. Annals of the New York Academy of Sciences 85 17145922
2010 CpG oligodeoxynucleotides as TLR9 agonists: therapeutic application in allergy and asthma. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy 81 20623989
2009 Emerging roles of TLR7 and TLR9 in murine SLE. Journal of autoimmunity 78 19846276
2021 The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA. Frontiers in immunology 76 33643304
2012 TLR9 is important for protection against intestinal damage and for intestinal repair. Scientific reports 74 22893852
2009 Bacterial DNA activates endothelial cells and promotes neutrophil adherence through TLR9 signaling. Journal of immunology (Baltimore, Md. : 1950) 72 19299739
2024 Formation of memory assemblies through the DNA-sensing TLR9 pathway. Nature 70 38538785
2013 FCRL3 promotes TLR9-induced B-cell activation and suppresses plasma cell differentiation. European journal of immunology 67 23857366
2014 TLR9 and BAFF: their expression in patients with IgA nephropathy. Molecular medicine reports 66 24993857
2017 BAD-LAMP controls TLR9 trafficking and signalling in human plasmacytoid dendritic cells. Nature communications 65 29030552
2015 Cell-intrinsic expression of TLR9 in autoreactive B cells constrains BCR/TLR7-dependent responses. Journal of immunology (Baltimore, Md. : 1950) 65 25681333
2020 TLR9 and beclin 1 crosstalk regulates muscle AMPK activation in exercise. Nature 63 32051584
2016 TLR2 and TLR9 modulate enteric nervous system inflammatory responses to lipopolysaccharide. Journal of neuroinflammation 61 27538577
2014 TLR9 is critical for glioma stem cell maintenance and targeting. Cancer research 61 25047528
2002 Bacterial CpG-DNA licenses TLR9. Current topics in microbiology and immunology 61 12467249
2006 TLR9 in health and disease. International reviews of immunology 60 16818370
2010 Therapeutic targeting of TLR9 inhibits cell growth and induces apoptosis in neuroblastoma. Cancer research 59 20935225
2022 Genetic dissection of TLR9 reveals complex regulatory and cryptic proinflammatory roles in mouse lupus. Nature immunology 56 36151396
2014 Bruton tyrosine kinase mediates TLR9-dependent human dendritic cell activation. The Journal of allergy and clinical immunology 56 24612681
2012 Low TLR9 expression defines an aggressive subtype of triple-negative breast cancer. Breast cancer research and treatment 55 22847512
2006 Homeostatic effects of TLR9 signaling in experimental colitis. Annals of the New York Academy of Sciences 53 17057215
2019 TLR9 signaling mediates adaptive immunity following systemic AAV gene therapy. Cellular immunology 52 31703913
2009 Expression of TLR2, TLR4, and TLR9 in dermatomyositis and polymyositis. Clinical rheumatology 52 19953283
2004 Mechanisms of TLR9 activation. Journal of endotoxin research 51 15588423
2021 Development of CpG oligodeoxynucleotide TLR9 agonists in anti-cancer therapy. Expert review of anticancer therapy 46 33831324
2022 TLR9: A friend or a foe. Life sciences 45 35963302
2021 TLR9 in MAFLD and NASH: At the Intersection of Inflammation and Metabolism. Frontiers in endocrinology 44 33584545
2016 Dectin-1 Controls TLR9 Trafficking to Phagosomes Containing β-1,3 Glucan. Journal of immunology (Baltimore, Md. : 1950) 44 26829985
2008 Expression of TLR9 within human glioblastoma. Journal of neuro-oncology 44 18253698
2019 Prophylactic TLR9 stimulation reduces brain metastasis through microglia activation. PLoS biology 43 30921319
2015 TLR7 and TLR9 ligands regulate antigen presentation by macrophages. International immunology 42 26567289
2023 Oxidized Mitochondrial DNA Engages TLR9 to Activate the NLRP3 Inflammasome in Myelodysplastic Syndromes. International journal of molecular sciences 41 36835307
2017 Role of TLR9 in Oncogenic Virus-Produced Cancer. Viral immunology 41 28151089
2012 Cofactors required for TLR7- and TLR9-dependent innate immune responses. Cell host & microbe 41 22423970
2014 The role of TLR9 polymorphism in susceptibility to pulmonary tuberculosis. Immunogenetics 40 25248338
2020 TLR9 deficiency alleviates doxorubicin-induced cardiotoxicity via the regulation of autophagy. Journal of cellular and molecular medicine 39 33140921
2006 TLR9-based immunotherapy for allergic disease. The American journal of medicine 39 17000223
2008 Protein kinase D1: a new component in TLR9 signaling. Journal of immunology (Baltimore, Md. : 1950) 38 18641342
2017 High-glucose induces tau hyperphosphorylation through activation of TLR9-P38MAPK pathway. Experimental cell research 36 28803064
2011 The role of DNA sensing and innate immune receptor TLR9 in otitis media. Innate immunity 36 21239460
2016 JNK-TLR9 signal pathway mediates allergic airway inflammation through suppressing melatonin biosynthesis. Journal of pineal research 35 26914888
2021 Self-DNA Sensing by cGAS-STING and TLR9 in Autoimmunity: Is the Cytoskeleton in Control? Frontiers in immunology 34 34084165
2012 Cell-specific TLR9 trafficking in primary APCs of transgenic TLR9-GFP mice. Journal of immunology (Baltimore, Md. : 1950) 34 23241879
2008 TLR9-mediated recognition of DNA. Handbook of experimental pharmacology 34 18071654
2014 Functional expression of TLR9 in esophageal cancer. Oncology reports 33 24647486
2022 Insights into innate immune activation via PS-ASO-protein-TLR9 interactions. Nucleic acids research 32 35848907
2017 Exogenous administration of mitochondrial DNA promotes ischemia reperfusion injury via TLR9-p38 MAPK pathway. Regulatory toxicology and pharmacology : RTP 31 28757323
2021 TLR9 expression in chronic lymphocytic leukemia identifies a promigratory subpopulation and novel therapeutic target. Blood 30 33512408
2019 HSV-1/TLR9-Mediated IFNβ and TNFα Induction Is Mal-Dependent in Macrophages. Journal of innate immunity 30 31851971
2018 B Cell Lymphoma Immunotherapy Using TLR9-Targeted Oligonucleotide STAT3 Inhibitors. Molecular therapy : the journal of the American Society of Gene Therapy 30 29433938
2010 Cell-specific expression of TLR9 isoforms in inflammation. Journal of autoimmunity 30 21115235
2006 DNA motifs suppressing TLR9 responses. Critical reviews in immunology 30 17341193
2018 The Effect and Mechanism of TLR9/KLF4 in FFA-Induced Adipocyte Inflammation. Mediators of inflammation 29 30662369
2012 TLR9- and Src-dependent expression of Krueppel-like factor 4 controls interleukin-10 expression in pneumonia. The European respiratory journal 29 22653776
2012 TLR4 and TLR9 are induced in oral lichen planus. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 27 22672741
2012 Understanding TLR9 action in Epstein-Barr virus infection. Frontiers in bioscience (Landmark edition) 26 22201799
2022 Anti-tumor immunity by transcriptional synergy between TLR9 and STING activation. International immunology 25 35419609
2019 Membrane TLR9 Positive Neutrophil Mediated MPLA Protects Against Fatal Bacterial Sepsis. Theranostics 25 31534550
2016 Computational Discovery and Experimental Confirmation of TLR9 Receptor Antagonist Leads. Journal of chemical information and modeling 25 27537371
2015 TLR9 gene region polymorphisms and susceptibility to tuberculosis in Vietnam. Tuberculosis (Edinburgh, Scotland) 25 25616954
2023 Rewiring innate and adaptive immunity with TLR9 agonist to treat osteosarcoma. Journal of experimental & clinical cancer research : CR 24 37365634
2019 CD82 controls CpG-dependent TLR9 signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 31408613
2019 Association of TLR4 and TLR9 gene polymorphisms and haplotypes with cervicitis susceptibility. PloS one 23 31365550
2024 Epstein-Barr virus suppresses N6-methyladenosine modification of TLR9 to promote immune evasion. The Journal of biological chemistry 22 38537697
2022 TLR9 Mediates Periodontal Aging by Fostering Senescence and Inflammaging. Journal of dental research 22 35918888
2017 TLR9-based immunotherapy for the treatment of allergic diseases. Immunotherapy 22 28303762
2017 Evaluation of TLR9 expression on PBMCs and CpG ODN-TLR9 ligation on IFN-α production in SLE patients. Immunopharmacology and immunotoxicology 21 28049380
2016 Mitochondrial DNA from hepatocytes as a ligand for TLR9: Drivers of nonalcoholic steatohepatitis? World journal of gastroenterology 21 27610009
2011 Dual or triple activation of TLR7, TLR8, and/or TLR9 by single-stranded oligoribonucleotides. Nucleic acid therapeutics 21 22196370
2016 TLR9 and its signaling pathway in multiple sclerosis. Journal of the neurological sciences 20 28131238

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