Affinage

TLR9

Toll-like receptor 9 · UniProt Q9NR96

Round 2 corrected
Length
1032 aa
Mass
115.9 kDa
Annotated
2026-04-28
130 papers in source corpus 23 papers cited in narrative 23 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TLR9 is an endosomal pattern recognition receptor that detects unmethylated CpG DNA and RNA:DNA hybrids to initiate innate immune signaling, with additional non-canonical roles in stress tolerance and neuronal function. At steady state TLR9 resides in the ER and, upon ligand uptake, translocates to endolysosomes where it directly binds CpG DNA at acidic pH; this trafficking requires UNC93B1, proteolytic processing by cathepsins, and a palmitoylation–depalmitoylation cycle mediated by DHHC3 and PPT1 that controls UNC93B1 release and downstream signaling output (PMID:14716310, PMID:23241879, PMID:38169466). The signaling outcome is compartment-determined: TLR9 activation in early endosomes drives IFN-α production whereas activation in late lysosomes drives NF-κB–dependent TNF responses, with accessory proteins BAD-LAMP, CD82, CD32, and Dectin-1 directing TLR9 to specific compartments (PMID:16864658, PMID:29030552, PMID:15668740, PMID:26829985). Genetic dissection in lupus-prone mice revealed that TLR9 possesses a MyD88-independent scaffold function that is B cell-intrinsic and protective against autoimmunity, separable from its ligand-dependent proinflammatory signaling (PMID:36151396).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 High

    Establishing TLR9 as the non-redundant receptor for bacterial CpG DNA resolved the long-standing question of how the innate immune system discriminates microbial from self-DNA.

    Evidence TLR9 knockout mice showing complete loss of CpG DNA responses across multiple readouts (proliferation, cytokines, DC maturation, Th1 polarization)

    PMID:11130078

    Open questions at the time
    • Ligand binding mechanism not yet defined
    • Subcellular site of receptor activation unknown
    • Signaling intermediates downstream of TLR9 not mapped
  2. 2004 High

    The discovery that TLR9 resides in the ER and must translocate to CpG-containing lysosomes to signal overturned the assumption that TLR activation occurs at the plasma membrane, establishing a new paradigm of intracellular innate receptor activation.

    Evidence Fluorescence microscopy and subcellular fractionation in primary DCs and macrophages showing ER residence and ligand-induced redistribution to LAMP1+ compartments with MyD88 co-recruitment

    PMID:14716310

    Open questions at the time
    • Molecular chaperone(s) required for ER-to-endosome trafficking not identified
    • Mechanism of pH-dependent ligand recognition not resolved
  3. 2004 High

    Demonstrating direct, pH-dependent, sequence-specific CpG DNA binding by TLR9 and identifying a CpG-binding domain resolved how ligand specificity is achieved in the acidic endolysosomal environment.

    Evidence Direct binding assays at acidic pH combined with site-directed mutagenesis abolishing both binding and NF-κB activation

    PMID:15307186

    Open questions at the time
    • Crystal structure of TLR9–CpG complex not available
    • Structural basis for methylation discrimination unresolved
  4. 2005 High

    Identifying that FcγRIIa (CD32) delivers DNA-containing immune complexes to TLR9-positive lysosomes in plasmacytoid DCs provided a mechanistic link between autoantibody-mediated uptake and TLR9 activation in systemic lupus erythematosus.

    Evidence Co-localization of CD32-internalized SLE immune complexes with TLR9 in lysosomes; receptor-blocking experiments abolishing PDC activation

    PMID:15668740

    Open questions at the time
    • Relative contribution of CD32-dependent vs -independent uptake in different DC subsets unclear
    • Whether other Fc receptors cooperate not tested
  5. 2006 High

    Demonstrating that the endosomal compartment of TLR9 activation—early endosome vs. late lysosome—determines whether IFN-α or NF-κB/maturation responses are elicited established compartmentalized signaling as a core principle of TLR9 biology.

    Evidence Endosomal fractionation and liposome-mediated redirection of CpG localization in primary human pDCs with cytokine readouts

    PMID:16864658

    Open questions at the time
    • Specific adaptor molecules distinguishing compartment-specific signaling not fully identified
    • How retention time in each compartment is regulated unknown
  6. 2006 High

    Showing that apical vs. basolateral TLR9 stimulation in polarized epithelial cells produces opposing NF-κB outcomes extended TLR9 compartment-dependent signaling to non-immune cells and implicated it in intestinal homeostasis.

    Evidence Polarized epithelial cell culture with NF-κB reporters and microarray, plus TLR9-deficient colitis model

    PMID:17128265

    Open questions at the time
    • Molecular mechanism of apical I-κBα ubiquitination without degradation not defined
    • In vivo epithelial-specific TLR9 contribution not separated from immune cell contribution
  7. 2012 High

    Identifying cell-type-specific cathepsin requirements for TLR9 proteolytic processing and demonstrating UNC93B1 as a universal regulator of this processing clarified how TLR9 activation is differentially tuned across immune lineages.

    Evidence TLR9-GFP transgenic mice analyzed in macrophages and B cells with cathepsin inhibitors and UNC93B1 3d mutant mice

    PMID:23241879

    Open questions at the time
    • Precise cleavage sites in TLR9 not mapped
    • Functional consequence of differential processing kinetics on signaling output not quantified
  8. 2013 Medium

    Discovery of a non-canonical TLR9–AMPK stress-protection pathway in cardiomyocytes and neurons, gated by UNC93B1 expression level, revealed that TLR9 functions beyond immunity as a metabolic sensor in non-immune cells.

    Evidence Primary cardiomyocyte and neuronal cultures showing CpG-induced AMP/ATP ratio increase, AMPK activation, and hypoxia protection without inflammatory cytokine induction; UNC93B1 manipulation switching pathway usage

    PMID:23479602

    Open questions at the time
    • Endogenous ligand triggering this pathway in vivo not identified
    • Whether AMPK activation is direct or through intermediate kinases unknown
    • Not independently replicated in a second laboratory
  9. 2015 High

    Establishing that DNase II generates the short CpG DNA fragments actually recognized by TLR9 in lysosomes redefined the ligand from intact CpG DNA to processed 11–12-mer fragments for at least some agonist classes.

    Evidence DNase II-deficient and enzymatically dead DCs showing loss of CpG-A responses; rescue by synthetic 3'-11-mer fragments

    PMID:25600358

    Open questions at the time
    • Whether all TLR9 ligand classes require DNase II processing not resolved
    • Structural basis for fragment-length preference unknown
  10. 2017 High

    Identification of BAD-LAMP as a trafficking regulator that directs TLR9 toward LAMP1+ late endosomes (promoting NF-κB/TNF) and away from VAMP3+/LAMP2+ IFN-α-inducing compartments provided a molecular handle on compartment-dependent signaling in pDCs.

    Evidence BAD-LAMP silencing and overexpression in primary human pDCs with compartment characterization and cytokine quantification

    PMID:29030552

    Open questions at the time
    • BAD-LAMP interaction surface on TLR9 not mapped
    • Whether BAD-LAMP regulates other endosomal TLRs not tested
  11. 2017 High

    Demonstration that glucocorticoid receptor suppresses TLR9-specific signaling by physically blocking IRAK1 K48-ubiquitination at K134 revealed a transcription-independent anti-inflammatory checkpoint unique to the TLR9 pathway.

    Evidence GR KO macrophages, IRAK1 K134 mutagenesis, ubiquitination assays, and Co-IP showing GR–IRAK1 interaction

    PMID:29038250

    Open questions at the time
    • Whether GR-IRAK1 interaction is direct or requires bridging factors not confirmed with purified proteins
    • In vivo relevance of K134-specific ubiquitination not tested
  12. 2022 High

    Genetic separation of TLR9 into three functional modes—ligand/MyD88-independent scaffold, ligand-dependent/MyD88-independent regulatory, and MyD88-dependent proinflammatory—overturned the linear receptor-signaling model and showed that TLR9's protective role in lupus operates via a B cell-intrinsic scaffold function.

    Evidence TLR9 K51E (no ligand binding) and P915H (no MyD88 recruitment) knockin alleles in lupus-prone mice with bone marrow chimeras

    PMID:36151396

    Open questions at the time
    • Molecular partners for the scaffold function not identified
    • Whether scaffold function involves other TIR-domain interactions unknown
  13. 2024 High

    Identification of a DHHC3/PPT1-mediated palmitoylation–depalmitoylation cycle on TLR9 C258/C265 that controls UNC93B1 release and signaling output provided the first lipid-modification mechanism governing TLR9 endosomal trafficking and activation.

    Evidence Mass spectrometry palmitoylation site mapping, C258/C265 mutagenesis, PPT1 KO/inhibition, DHHC3 manipulation with cytokine readouts in vivo and in vitro

    PMID:38169466

    Open questions at the time
    • Whether other palmitoyl-acyltransferases contribute redundantly not excluded
    • Structural consequences of palmitoylation on TLR9–UNC93B1 interface not resolved
  14. 2024 Medium

    Discovery that learning-induced DNA damage activates neuronal TLR9 for memory formation, linking TLR9 to centrosome function and ciliogenesis in neurons, opened an entirely non-immune role for TLR9 in cognitive processes.

    Evidence Neuron-specific Tlr9 knockdown impairing contextual fear memory; gene profiling showing centrosome, DNA repair, and perineuronal net pathways

    PMID:38538785

    Open questions at the time
    • Whether endogenous nuclear DNA fragments are the physiological TLR9 ligand in neurons is unconfirmed
    • Mechanism linking TLR9 to centrosome function not characterized
    • Single study, not independently replicated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of molecular partners mediating TLR9's MyD88-independent scaffold function, the structural basis of compartment-specific signaling complex assembly, and whether neuronal and cardiomyocyte TLR9 functions use the same or distinct ligand-processing and trafficking machinery as immune cells.
  • Scaffold function partners unidentified
  • No high-resolution structure of full-length TLR9 in complex with signaling adaptors
  • Endogenous ligands in non-immune contexts not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0140299 molecular sensor activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005764 lysosome 4 GO:0005768 endosome 4 GO:0005783 endoplasmic reticulum 3 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-168256 Immune System 9 R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 3
Partners
CD82IRAK1LAMP5MYD88PPT1TRAF6UNC93B1ZDHHC3
Complex memberships
TLR9–MyD88–IRAK1–TRAF6 myddosomeTLR9–UNC93B1 trafficking complex

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 TLR9 is the essential pattern recognition receptor for bacterial CpG DNA; TLR9-deficient mice fail to respond to CpG DNA stimulation, including splenocyte proliferation, inflammatory cytokine production, dendritic cell maturation, and in vivo Th1 responses, establishing TLR9 as the receptor that distinguishes bacterial from self-DNA. TLR9 knockout mice, in vitro stimulation assays, in vivo cytokine measurement Nature High 11130078
2004 TLR9 resides in the endoplasmic reticulum at steady state and translocates to CpG DNA-containing lysosomal compartments upon ligand uptake, where it co-accumulates with MyD88 and initiates signaling; this established a previously unknown mechanism of immune receptor activation requiring ER-to-lysosome translocation. Fluorescence microscopy, subcellular fractionation, co-localization studies in dendritic cells and macrophages, ligand-binding studies Nature immunology High 14716310
2004 TLR9 binds directly and sequence-specifically to single-stranded unmethylated CpG-DNA at acidic pH (6.5–5.0) matching endosomal/lysosomal conditions; a CpG-DNA binding domain homologous to methyl-CpG-binding proteins was identified, and amino acid substitutions in this region abrogated both CpG-DNA binding and NF-κB activation. Direct binding assays, site-directed mutagenesis, NF-κB reporter assays European journal of immunology High 15307186
2004 Human TLR9 gene transcription is regulated by four cis-acting elements (CRE, 5'-PU box, 3'-PU box, C/EBP site) interacting with CREB1, Ets2, Elf1, Elk1, and C/EBPα transcription factors; CpG DNA-mediated suppression of TLR9 transcription involves c-Jun and NF-κB p65. Reporter gene analysis, EMSA, transcription factor identification in human myeloma cells Journal of immunology Medium 15294971
2005 DNA-containing immune complexes in lupus serum activate plasmacytoid DCs through cooperative interaction between TLR9 and FcγRIIa (CD32); CD32 delivers SLE immune complexes to intracellular lysosomes containing TLR9, inducing a signaling cascade leading to PDC activation. Subcellular co-localization microscopy, functional assays with CD32+ vs CD32- PDCs, cytokine measurement The Journal of clinical investigation High 15668740
2005 DNA-PKcs, not TLR9, is the primary mediator of CpG-DNA-induced Akt phosphorylation and activation; in vitro reconstitution showed DNA-PK directly phosphorylates Akt, and DNA-PKcs associates with Akt upon CpG-DNA stimulation to trigger transient nuclear translocation of Akt in macrophages. DNA-PKcs and TLR9 KO macrophages, in vitro kinase assay with purified proteins, co-immunoprecipitation, nuclear fractionation The EMBO journal High 15678105
2006 Apical vs. basolateral TLR9 signaling in polarized intestinal epithelial cells produces distinct transcriptional responses: basolateral TLR9 activates NF-κB via IκBα degradation, whereas apical TLR9 stimulation causes ubiquitinated IκB accumulation without NF-κB activation and confers tolerance to subsequent TLR challenges, maintaining colonic homeostasis. Polarized epithelial cell culture, NF-κB reporter assays, cDNA microarray, TLR9-deficient mouse model of colitis Nature cell biology High 17128265
2006 The endosomal location of TLR9 activation—not oligonucleotide valency—determines the nature of the plasmacytoid DC response: TfR+ early endosomes drive IFN-α production while LAMP1+ lysosomes drive PDC maturation; altering CpG oligonucleotide localization by encapsulation redistributes the response. Endosomal fractionation, confocal microscopy, liposome encapsulation to redirect compartmental localization, cytokine assays in primary human PDCs The Journal of experimental medicine High 16864658
2008 Protein kinase D1 (PKD1) is activated downstream of TLR9 via a pathway requiring endosomal pH, MyD88, and IRAK1; upon CpG-B DNA stimulation PKD1 interacts with the TLR9/MyD88/IRAK1/TRAF6 complex and is required for NF-κB and MAPK activation and subsequent cytokine expression. PKD1 knockdown (siRNA), Co-immunoprecipitation, kinase activity assays, NF-κB reporter assays in macrophages Journal of immunology Medium 18641342
2010 TLR9 is required for innate immune response to CpG DNA in chicken macrophages via a distinct receptor (chTLR21), demonstrating convergent evolution; in mammalian cells, TLR9 localizes to the same intracellular compartments as chTLR21, and endosomal maturation is required for functional signaling. Receptor cloning, HEK293 transfection, gene silencing in chicken macrophages, confocal microscopy, pharmacological inhibition Journal of immunology Medium 20498358
2012 Cell-type-specific differences exist in TLR9 trafficking and proteolytic processing: in macrophages, TLR9 cleavage requires both cathepsins L and S, whereas in B cells only cathepsin L is required; processing rate is faster in B cells, which show predominantly endolysosomal TLR9 localization at rest; UNC93B1 expression level is tightly correlated with TLR9-GFP cleavage and is required for processing in all cell types. Transgenic TLR9-GFP mice, live-cell imaging, pharmacological cathepsin inhibition, UNC93B1 3d mutant mice Journal of immunology High 23241879
2013 TLR9 stimulation in cardiomyocytes and neurons activates a non-canonical pathway that reduces energy substrates, raises the AMP/ATP ratio, and activates AMPK to increase stress tolerance against hypoxia, without inducing canonical inflammatory responses; UNC93B1 expression acts as a pivotal switch regulating subcellular localization of TLR9 and determines which signaling pathway is activated in a cell-type-specific manner. Primary cardiomyocyte and neuronal culture, TLR9 stimulation, AMPK activity assays, metabolic measurements, UNC93B1 manipulation, hypoxia survival assays Proceedings of the National Academy of Sciences of the United States of America Medium 23479602
2014 RNA:DNA hybrids are recognized by TLR9 as a novel molecular pattern; MyD88-dependent signaling is essential for cytokine responses induced by RNA:DNA hybrids containing viral sequences in dendritic cells. MyD88-deficient cells, TLR9-specific knockdown/KO, cytokine production assays, synthetic RNA:DNA hybrids The EMBO journal Medium 24514026
2015 DNase II enzymatic activity is required for TLR9 activation by CpG-A (but not CpG-B) and by bacterial genomic DNA; DNase II cleaves CpG-A from 20-mer to 11–12-mer fragments, and these 3'-11-mer fragments activate DNase II-deficient DCs, demonstrating that TLR9 responds to DNA fragments generated by lysosomal DNase II rather than intact DNA. DNase II-deficient DCs, enzymatically inactive DNase II mutants, co-localization microscopy, stimulation with defined DNA fragments Nature communications High 25600358
2016 Dectin-1 controls TLR9 trafficking to phagosomes containing β-1,3 glucan via spleen tyrosine kinase (Syk) activation; phagosomal acidification and Dectin-1-mediated Syk signaling are both required for TLR9 accumulation at fungal phagosomes, and Dectin-1 regulates TLR9-dependent gene expression. Confocal microscopy, pharmacological inhibition of Syk and endosomal acidification, Dectin-1-deficient cells, gene expression assays Journal of immunology Medium 26829985
2017 BAD-LAMP (LAMP5) controls TLR9 trafficking to LAMP1+ late endosomes in plasmacytoid DCs, promoting NF-κB activation and TNF production; a separate VAMP3+/LAMP2+/LAMP1- compartment supports IFN-α production, and BAD-LAMP silencing enhances TLR9 retention in this IFN-α-inducing compartment, while BAD-LAMP overexpression suppresses IFN-α. siRNA silencing, confocal microscopy, compartment characterization, cytokine measurement in primary human pDCs Nature communications High 29030552
2017 Glucocorticoid receptor (GR) suppresses TLR9-induced inflammation via a transcription-independent mechanism by physically interacting with IRAK1 and blocking β-TrCP-mediated K48-linked ubiquitination of IRAK1 at Lys134; this prevents membrane-to-cytoplasm trafficking of TRAF6 and TAK1 and downstream NF-κB/MAPK activation, an effect specific to TLR9 and not TLR4. Co-immunoprecipitation, site-directed mutagenesis (K134 IRAK1), GR KO macrophages, ubiquitination assays, cytokine measurement Journal of immunology High 29038250
2018 Dengue virus (an RNA virus) activates TLR9 in human dendritic cells by inducing release of mitochondrial DNA (mtDNA) into the cytosol; this involves reactive oxygen species generation, inflammasome activation, disruption of TFAM-mtDNA association, and activation of mitochondrial permeability transition pores; both TLR9 and cGAS comparably contribute to DENV-induced immune activation. TLR9 and cGAS siRNA knockdown, TLR9 KO mouse bone marrow-derived DCs, mtDNA release quantification, ROS measurement, cytokine assays EMBO reports Medium 29880709
2019 CD82 (a tetraspanin) is a key regulator of TLR9 trafficking and signaling; TLR9 and CD82 associate in the ER and post-ER compartments of macrophages, and CD82 is essential for TLR9-dependent myddosome formation and NF-κB nuclear translocation in response to CpG stimulation. Co-immunoprecipitation, confocal microscopy, CD82-deficient macrophages, NF-κB nuclear translocation assays, myddosome complex analysis FASEB journal Medium 31408613
2022 Genetic dissection using TLR9 point mutants in lupus-prone mice revealed that TLR9 has distinct signaling modes: (1) a ligand- and MyD88-independent 'scaffold' protective function; (2) a ligand-dependent but MyD88-independent regulatory signaling function (B cell-intrinsic, restraining age-associated B cells and plasmablasts); and (3) a MyD88-dependent proinflammatory signaling function. TLR9 point mutant knockin mice (TLR9K51E lacking ligand binding; TLR9P915H lacking MyD88 binding), bone marrow chimeras, flow cytometry, disease phenotyping Nature immunology High 36151396
2024 TLR9 undergoes a cycle of S-palmitoylation and depalmitoylation that controls its endosomal signaling: DHHC3 palmitoylates TLR9 at C258 and C265 in the Golgi and regulates its trafficking to endosomes; PPT1 removes S-palmitoylation from TLR9 in lysosomes and facilitates TLR9 release from UNC93B1, promoting IFN-α secretion by pDCs and TNF by macrophages. Mass spectrometry (palmitoylation site identification), site-directed mutagenesis (C258/C265), PPT1 KO/inhibition, DHHC3 manipulation, biochemical palmitoylation assays, cytokine measurements in vitro and in vivo Nature communications High 38169466
2024 TLR9 signaling in hippocampal CA1 neurons is required for memory formation; learning induces dsDNA breaks and nuclear envelope ruptures in discrete neuronal clusters, triggering TLR9 activation; neuron-specific Tlr9 knockdown impairs contextual fear memory and TLR9 has an essential role in centrosome function including DNA damage repair, ciliogenesis, and perineuronal net formation. Neuron-specific Tlr9 knockdown, contextual fear conditioning, gene expression profiling of CA1 neuron clusters, centrosome functional assays, imaging of dsDNA breaks Nature Medium 38538785
2024 EBV suppresses TLR9 expression by downregulating N6-methyladenosine (m6A) modification of TLR9 mRNA; EBNA1 promotes K48-linked ubiquitin-proteasome degradation of METTL3 (m6A writer), reducing TLR9 mRNA stability; YTHDF1 acts as an m6A reader that enhances TLR9 translation, and loss of METTL3/YTHDF1 reduces TLR9 protein expression and impairs TLR9-dependent B cell responses. METTL3/YTHDF1 knockdown, m6A site mapping, ubiquitination assays, protein stability assays, B cell functional assays The Journal of biological chemistry Medium 38537697

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 A Toll-like receptor recognizes bacterial DNA. Nature 4949 11130078
2002 Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. Journal of immunology (Baltimore, Md. : 1950) 1520 11970999
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2001 Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. The Journal of experimental medicine 1457 11561001
1998 A family of human receptors structurally related to Drosophila Toll. Proceedings of the National Academy of Sciences of the United States of America 1291 9435236
2013 Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nature genetics 1192 23974872
2006 Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors. Immunity 1139 16979567
2004 TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nature immunology 1069 14716310
2011 Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nature genetics 1068 21926972
2005 Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nature medicine 981 15723075
2004 Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. Journal of immunology (Baltimore, Md. : 1950) 973 15356140
2005 Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. The Journal of experimental medicine 739 16230478
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2005 Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. The Journal of clinical investigation 666 15668740
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2003 A role for Toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells. Blood 529 12560217
2011 Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. Journal of immunology (Baltimore, Md. : 1950) 477 21398612
2006 Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nature cell biology 471 17128265
2003 SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nature immunology 467 12925853
2009 Immunotherapeutic applications of CpG oligodeoxynucleotide TLR9 agonists. Advanced drug delivery reviews 453 19211030
2001 Cutting edge: Role of Toll-like receptor 9 in CpG DNA-induced activation of human cells. Journal of immunology (Baltimore, Md. : 1950) 443 11564765
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2010 Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. Journal of immunology (Baltimore, Md. : 1950) 436 20100933
2004 Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner. European journal of immunology 408 15307186
2016 Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. The Journal of clinical investigation 401 26808498
2003 The role of PI3K in immune cells. Nature immunology 391 12660731
2002 Toll-like receptors as adjuvant receptors. Biochimica et biophysica acta 359 11909637
2000 Three novel mammalian toll-like receptors: gene structure, expression, and evolution. European cytokine network 357 11022119
2007 Development of TLR9 agonists for cancer therapy. The Journal of clinical investigation 347 17476348
2008 Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. The New England journal of medicine 345 18946062
2000 Cloning and characterization of a sub-family of human toll-like receptors: hTLR7, hTLR8 and hTLR9. European cytokine network 321 11022120
2008 TLR9 as a key receptor for the recognition of DNA. Advanced drug delivery reviews 320 18262306
2008 Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene 318 18176597
2006 Properties regulating the nature of the plasmacytoid dendritic cell response to Toll-like receptor 9 activation. The Journal of experimental medicine 311 16864658
2010 TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature 301 20559388
2008 Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections. Nature medicine 300 18806803
2011 TLR9 and the NLRP3 inflammasome link acinar cell death with inflammation in acute pancreatitis. Gastroenterology 241 21439959
2010 Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis. BMC cancer 194 21129170
2018 Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency. The EMBO journal 169 29632021
2010 Chicken TLR21 is an innate CpG DNA receptor distinct from mammalian TLR9. Journal of immunology (Baltimore, Md. : 1950) 167 20498358
2012 TLR7 and TLR9 in SLE: when sensing self goes wrong. Immunologic research 163 22434514
2024 Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice. Nature communications 151 38169466
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 134 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 122 25600358
2010 Study of TLR3, TLR4, and TLR9 in prostate carcinomas and their association with biochemical recurrence. Cancer immunology, immunotherapy : CII 121 20978888
2008 Role of TLR9 in hepatic stellate cells and experimental liver fibrosis. Biochemical and biophysical research communications 117 18760996
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 115 25930080
2019 Below the surface: The inner lives of TLR4 and TLR9. Journal of leukocyte biology 111 30900780
2011 Overexpression of TLR3, TLR4, TLR7 and TLR9 in esophageal squamous cell carcinoma. World journal of gastroenterology 107 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 92 24169824
2018 Infection with the dengue RNA virus activates TLR9 signaling in human dendritic cells. EMBO reports 91 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 88 14552833
2010 Targeting the TLR9-MyD88 pathway in the regulation of adaptive immune responses. Expert opinion on therapeutic targets 86 20560798
2006 TLR9 and the recognition of self and non-self nucleic acids. Annals of the New York Academy of Sciences 85 17145922
2020 B cell-intrinsic TLR9 expression is protective in murine lupus. The Journal of clinical investigation 84 32191633
2009 CpG oligodeoxynucleotides as TLR9 agonists: therapeutic applications in cancer. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy 84 19894778
2019 PINK1 attenuates mtDNA release in alveolar epithelial cells and TLR9 mediated profibrotic responses. PloS one 83 31170232
2013 TLR9 mediates cellular protection by modulating energy metabolism in cardiomyocytes and neurons. Proceedings of the National Academy of Sciences of the United States of America 80 23479602
2010 CpG oligodeoxynucleotides as TLR9 agonists: therapeutic application in allergy and asthma. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy 79 20623989
2019 Chronic TLR7 and TLR9 signaling drives anemia via differentiation of specialized hemophagocytes. Science (New York, N.Y.) 78 30630901
2009 Emerging roles of TLR7 and TLR9 in murine SLE. Journal of autoimmunity 78 19846276
2004 Transcriptional regulation of the human TLR9 gene. Journal of immunology (Baltimore, Md. : 1950) 77 15294971
2021 The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA. Frontiers in immunology 75 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
2008 A combination of Lox-1 and Nox1 regulates TLR9-mediated foam cell formation. Cellular signalling 70 18817866
2005 TLR9 pathway is involved in adjuvant effects of plasmid DNA-based vaccines. Vaccine 67 15652668
2014 TLR9 and BAFF: their expression in patients with IgA nephropathy. Molecular medicine reports 65 24993857
2024 Formation of memory assemblies through the DNA-sensing TLR9 pathway. Nature 64 38538785
2017 BAD-LAMP controls TLR9 trafficking and signalling in human plasmacytoid dendritic cells. Nature communications 64 29030552
2015 Cell-intrinsic expression of TLR9 in autoreactive B cells constrains BCR/TLR7-dependent responses. Journal of immunology (Baltimore, Md. : 1950) 64 25681333
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
2016 TLR2 and TLR9 modulate enteric nervous system inflammatory responses to lipopolysaccharide. Journal of neuroinflammation 59 27538577
2010 Therapeutic targeting of TLR9 inhibits cell growth and induces apoptosis in neuroblastoma. Cancer research 59 20935225
2014 Bruton tyrosine kinase mediates TLR9-dependent human dendritic cell activation. The Journal of allergy and clinical immunology 56 24612681
2010 Impaired innate immunity in Tlr4(-/-) mice but preserved CD8+ T cell responses against Trypanosoma cruzi in Tlr4-, Tlr2-, Tlr9- or Myd88-deficient mice. PLoS pathogens 56 20442858
2012 Low TLR9 expression defines an aggressive subtype of triple-negative breast cancer. Breast cancer research and treatment 55 22847512
2022 Genetic dissection of TLR9 reveals complex regulatory and cryptic proinflammatory roles in mouse lupus. Nature immunology 53 36151396
2006 Homeostatic effects of TLR9 signaling in experimental colitis. Annals of the New York Academy of Sciences 53 17057215
2004 Mechanisms of TLR9 activation. Journal of endotoxin research 51 15588423
2019 TLR9 signaling mediates adaptive immunity following systemic AAV gene therapy. Cellular immunology 50 31703913
2012 Lymphotoxin β receptor activation on macrophages induces cross-tolerance to TLR4 and TLR9 ligands. Journal of immunology (Baltimore, Md. : 1950) 47 22357629
2021 Development of CpG oligodeoxynucleotide TLR9 agonists in anti-cancer therapy. Expert review of anticancer therapy 44 33831324
2016 Dectin-1 Controls TLR9 Trafficking to Phagosomes Containing β-1,3 Glucan. Journal of immunology (Baltimore, Md. : 1950) 44 26829985
2021 TLR9 in MAFLD and NASH: At the Intersection of Inflammation and Metabolism. Frontiers in endocrinology 43 33584545
2008 Redundant role of TLR9 for anti-Candida host defense. Immunobiology 43 18950591
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