Affinage

TLR8

Toll-like receptor 8 · UniProt Q9NR97

Length
1041 aa
Mass
119.8 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TLR8 is an endosomal innate-immune sensor of single-stranded RNA that signals through its IL-1 receptor-homologous cytoplasmic TIR domain to drive NF-κB and proinflammatory gene expression (PMID:11022120, PMID:16737960). Productive sensing requires upstream processing and trafficking: TLR8 associates with UNC93B1 and localizes to early endosomes and ER, with its transmembrane and TIR domains directing endosomal targeting (PMID:22164301); it undergoes furin-like convertase- and cathepsin-dependent proteolytic cleavage at the LRR14–LRR15 insertion loop (PMID:25297876); and its ligands are catabolic uridine- and purine-2',3'-cyclophosphate-terminated oligoribonucleotides generated by the lysosomal endoribonuclease RNase T2, which dock into TLR8's two distinct binding pockets (PMID:31778653). A five-residue motif following LRR-14, absent in rodents, confers species-specific ligand recognition and underlies human-restricted responsiveness (PMID:18322178, PMID:20004021). Downstream, TLR8 engages a distinct activation route requiring IRAK and IRAK4 (independent of their kinase activity) and MEKK3, proceeding through IKKγ phosphorylation rather than the canonical TAK1/IKKαβ axis used by IL-1R (PMID:16737960), and it couples IRAK-1 to an IRF5-dependent type I IFN response (PMID:31214180). Through these mechanisms TLR8 detects bacterial and mitochondrial RNA (UR/URR motifs), viral RNA, and self-RNA, distinguishing live from dead bacteria as a viability signal and activating the NLRP3 inflammasome to produce IL-1β (PMID:26101323, PMID:26545385, PMID:29556002, PMID:26928328). TLR8 also acts as a negative regulator of TLR7 expression and signaling in dendritic cells, restraining spontaneous autoimmunity (PMID:20811154, PMID:24474776). Beyond immunity, TLR8 functions in neurons to suppress neurite outgrowth, drive dendritic pruning via MyD88/MAPK signaling, and mediate neuropathic pain through ERK/p38 activation, with miR-21 acting as an endogenous ligand (PMID:18000403, PMID:29777026, PMID:30455267). Gain-of-function TLR8 variants cause a childhood-onset inborn error of immunity with proinflammatory T-cell activation and impaired B-cell maturation (PMID:33512449). TLR8 escapes X-chromosome inactivation in human monocytes and T cells, contributing to sex-biased immune responses (PMID:37723501).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2000 Medium

    Established TLR8 as a TLR-family receptor whose IL-1R-like TIR domain can engage NF-κB, defining it as an innate signaling receptor encoded on the X chromosome.

    Evidence Molecular cloning, sequence analysis, and NF-κB reporter assay of constitutively active TLR8 in transfected cells

    PMID:11022120

    Open questions at the time
    • No physiological ligand identified
    • No mechanistic dissection of the downstream cascade
  2. 2006 High

    Resolved the TLR8 signaling cascade as distinct from IL-1R, showing it requires IRAK/IRAK4 (kinase-independent) and MEKK3 and uses IKKγ phosphorylation rather than the canonical TAK1/IKKαβ route.

    Evidence Genetic epistasis in TAK1−/− and MEKK3−/− MEFs, IRAK-deficient cells, kinase-dead rescue, and IKK-complex immunoblotting

    PMID:16737960

    Open questions at the time
    • Did not identify the natural ligand driving this cascade
    • Mechanism of IKKγ phosphorylation not resolved
  3. 2008 High

    Defined TLR8 as a sensor of specific ssRNA motifs functionally separable from TLR7 and species-restricted, explaining why human and mouse TLR8 behave differently.

    Evidence TLR-transfected reporter cells, primary human monocyte/myeloid DC stimulation, and cross-species comparison

    PMID:18322178

    Open questions at the time
    • Structural basis of motif recognition not defined
    • Source of physiological RNA ligand in vivo not established
  4. 2009 High

    Mapped the molecular determinant of species-specific ligand recognition to a five-residue motif after LRR-14, decoupling ligand sensing from dimerization and localization.

    Evidence Cross-species sequence alignment and deletion mutagenesis of hTLR8 with NF-κB reporter readout

    PMID:20004021

    Open questions at the time
    • Did not show direct ligand contact by the motif
    • No structural model of the engaged receptor
  5. 2011 High

    Identified UNC93B1 as a physical partner required for TLR8 endosomal trafficking and signaling, placing TLR8 function in early endosomes/ER.

    Evidence Co-immunoprecipitation, confocal microscopy, subcellular fractionation, and domain-truncation analysis in HeLa and human monocytes

    PMID:22164301

    Open questions at the time
    • Mechanism of UNC93B1-mediated trafficking not detailed
    • Relationship between trafficking and proteolytic maturation unresolved
  6. 2014 High

    Established that TLR8 maturation requires proteolytic cleavage at the LRR14–LRR15 loop by furin-like convertases and cathepsins, distinguishing its processing from TLR7/9.

    Evidence Immunoblotting of endogenous TLR8 in primary human cells with furin/cathepsin inhibitors and domain-deletion mutants

    PMID:25297876

    Open questions at the time
    • Exact cleavage sites not mapped
    • Functional requirement of cleavage for ligand binding not directly tested
  7. 2015 High

    Identified TLR8 as the human sensor of bacterial and mitochondrial UR/URR RNA motifs, functioning as the human counterpart of mouse TLR13.

    Evidence siRNA/knockout and overexpression in macrophages and THP-1 cells, lysosomal inhibitors, synthetic oligoribonucleotides, and infection models

    PMID:26101323 PMID:26545385

    Open questions at the time
    • Did not define the enzyme generating the agonistic fragments
    • Structural binding mode of the motifs not resolved
  8. 2019 High

    Identified RNase T2 as the non-redundant upstream enzyme that generates TLR8's agonistic uridine- and purine-2',3'-cyclophosphate-terminated ligands, defining how RNA is converted into a TLR8 signal.

    Evidence RNase T2 knockout/knockdown with reconstitution, biochemical characterization of degradation products, and TLR8 reporter assays

    PMID:31778653

    Open questions at the time
    • Coordination between RNase T2 cleavage and RNase 2/other nucleases not fully resolved
    • In vivo requirement across infection contexts not established
  9. 2017 High

    Defined the resting-state structure of the TLR8 homodimer and a druggable protein-protein interface, showing antagonists lock the preformed dimer inactive.

    Evidence X-ray crystallography of two TLR8-ligand complexes with NF-κB and cytokine functional validation in primary cells and patient specimens

    PMID:29155428 PMID:30100350

    Open questions at the time
    • Active-state conformational change upon agonist binding not captured
    • Allosteric coupling to the cytoplasmic TIR domain not structurally defined
  10. 2010 High

    Revealed a regulatory function whereby TLR8 negatively controls TLR7 expression and signaling, preventing spontaneous autoimmunity, and showed cell-type-specific division of labor with TLR9.

    Evidence Tlr8−/− single and Tlr8/9 double-knockout mice with TLR7 hyperresponsiveness, autoantibody, and disease readouts

    PMID:20811154 PMID:24474776

    Open questions at the time
    • Molecular mechanism by which TLR8 restrains TLR7 expression not defined
    • Mouse TLR8 lacks RNA-ligand responsiveness, complicating translation to human
  11. 2019 High

    Established TLR8 as a dominant pyogenic-bacteria sensor and revealed that cell-surface TLR signaling cross-inhibits TLR8 by modifying IRAK-1, which is required for the TLR8-IRF5 axis.

    Evidence Selective TLR8 antagonist, IRAK-1 siRNA, TLR agonist combinations, and IRAK-1 immunoblotting in primary human monocytes

    PMID:31214180

    Open questions at the time
    • Nature of the IRAK-1 modification not biochemically defined
    • Direct TLR8–IRF5 interaction not demonstrated
  12. 2018 High

    Demonstrated that TLR8 detects live-bacteria RNA as a viability discriminator shaping TFH differentiation and antibody responses, with a hypermorphic human variant linked to protective BCG immunity.

    Evidence Live vs. heat-killed bacteria, TLR8 agonists, human/porcine APC and TFH assays, pig vaccination model, and human BCG cohort genotyping

    PMID:29556002

    Open questions at the time
    • Molecular basis of live/dead RNA discrimination not fully resolved
    • Causal mechanism of the protective polymorphism not established
  13. 2018 High

    Extended TLR8 function to the nervous system, showing it senses miR-21 and signals through ERK/p38 MAPK to drive neuropathic pain and dendritic pruning rather than axonal growth.

    Evidence Tlr8−/− mice, in utero electroporation, agonist injection, miR-21 inhibition, ERK/p38 assays, electrophysiology, and confocal localization in DRG/TG neurons

    PMID:29777026 PMID:30455267 PMID:33355900 PMID:36474072

    Open questions at the time
    • Endosomal trafficking machinery in neurons not defined
    • Relationship between neuronal and immune signaling outputs unresolved
  14. 2022 High

    Showed that costimulation reprograms TLR8 signaling, with CXCL4 redirecting TBK1/IKKε to couple with IRF5 to amplify inflammatory transcription and NLRP3-driven IL-1β while attenuating IFN.

    Evidence Phosphoproteomics, ChIP-seq/ATAC-seq, kinase inhibitors, IRF5 knockdown, and NLRP3 assays in human monocytes/macrophages

    PMID:26928328 PMID:35701499

    Open questions at the time
    • Direct kinase–IRF5 contacts not structurally defined
    • Generality across other costimuli unknown
  15. 2021 Medium

    Linked TLR8 directly to human disease by showing gain-of-function variants cause a childhood-onset inborn error of immunity with constitutive/enhanced activity, including a destabilizing variant that loses TLR7 restraint.

    Evidence Patient iPSC-derived myeloid cells, transfection-based TLR8 activity assays, immune phenotyping, and mutant-vs-WT functional comparison

    PMID:33512449 PMID:34981838

    Open questions at the time
    • Structural basis of constitutive activity not resolved
    • Single-study/single-family cohorts limit genotype-phenotype breadth
  16. 2023 Medium

    Provided a molecular basis for sex-biased TLR8 immunity by showing TLR8 escapes X-chromosome inactivation, producing higher protein levels in female cells.

    Evidence RNA FISH relative to X-chromosome territories plus Western blot and flow cytometry across sex groups in primary immune cells

    PMID:37723501

    Open questions at the time
    • Functional consequence of biallelic expression on signaling output not quantified
    • Contribution to specific autoimmune phenotypes not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How agonist binding at the two RNA pockets is allosterically transmitted across the cleaved, dimeric ectodomain to the TIR domain to selectively engage the MEKK3/IRAK-IRF5 cascade remains unresolved.
  • No active-state TLR8 structure with bound agonist coupled to TIR signaling
  • Mechanism distinguishing NF-κB vs IRF5 output not defined
  • Direct biochemical TLR8–IRF5/MEKK3 contacts unconfirmed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0060089 molecular transducer activity 3 GO:0038024 cargo receptor activity 2
Localization
GO:0005768 endosome 3 GO:0005764 lysosome 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 2
Partners
IRAK1IRAK4IRF5MEKK3SOCS1UNC93B1

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 TLR8 contains an ectodomain with multiple leucine-rich repeats (LRRs) and a cytoplasmic TIR domain homologous to the IL-1 receptor. Expression of constitutively active TLR8 stimulates NF-κB signaling. TLR8 gene is located on the X chromosome. Molecular cloning, sequence analysis, NF-κB reporter assay in transfected cells European cytokine network Medium 11022120
2006 TLR8-mediated NF-κB and JNK activation require IRAK and IRAK4 (but not their kinase activities), are TAK1-independent, and are completely abolished in MEKK3-deficient cells. TLR8 ligands induce IKKγ phosphorylation but not IKKα/β phosphorylation or IKKγ ubiquitination (unlike IL-1R signaling), indicating a distinct NF-κB activation pathway downstream of TLR8. Genetic epistasis using TAK1−/− and MEKK3−/− mouse embryonic fibroblasts, IRAK-deficient human cells, kinase-inactive mutant rescue, immunoblotting for IκBα phosphorylation and IKK complex components The Journal of biological chemistry High 16737960
2008 Defined single-stranded RNA sequence motifs (TLR8-specific) selectively activate human TLR8 without stimulating TLR7. These TLR8 RNA motifs fail to induce IFN-α from plasmacytoid DCs but induce Th1-like and proinflammatory cytokines from monocytes and myeloid DCs. TLR8 RNA ligand responsiveness is species-specific (human and bovine but not mouse, rat, or porcine). TLR-transfected reporter cell lines, primary human immune cell stimulation, species comparison, TLR-specific inhibitory sequences Journal of immunology High 18322178
2009 A five-amino-acid motif in the TLR8 ectodomain immediately following LRR-14 (absent in rodent TLR8) is essential for species-specific ligand recognition. Deletion of this motif abolishes ligand responsiveness of human TLR8, while it is not required for self-dimerization or intracellular localization. Multiple species sequence alignment, deletion mutagenesis of hTLR8, NF-κB reporter assays in transfected cells Molecular immunology High 20004021
2011 UNC93B1 physically associates with human TLR8 and is required for TLR8-mediated signaling. TLR8 localizes to early endosomes and the ER (not late endosomes or lysosomes) in human monocytes. The transmembrane domain and TIR domain of TLR8 are required for proper targeting to the early endosome. Co-immunoprecipitation, confocal microscopy, subcellular fractionation, tail-truncation mutant analysis in HeLa transfectants and human monocytes PloS one High 22164301
2011 TLR8 senses bacterial RNA released within phagosomal vacuoles during Borrelia burgdorferi infection in human monocytes, mediating production of TNF-α, IL-6, and IL-10, and exclusively driving IRF7-mediated IFN-β transcription. TLR2 and TLR8 cooperate for cytokine responses in phagosomes; TLR8 is solely responsible for IFN-β induction. IRF7 is translocated to the nucleus in Bb-infected monocytes. TLR-specific inhibitory immunoregulatory sequences (IRS957), confocal and epifluorescence microscopy for TLR2/TLR8 colocalization with bacteria, IRF7 nuclear translocation assay, cytokine/mRNA measurement Proceedings of the National Academy of Sciences of the United States of America High 21321205
2014 TLR8 undergoes proteolytic cleavage in human monocytes and macrophages in a manner distinct from TLR7/9. The insertion loop between LRR14 and LRR15 is indispensable for cleavage and stepwise processing of the N-terminal fragment. Both furin-like proprotein convertase and cathepsins contribute to TLR8 cleavage in early/late endosomes. Immunoblotting of endogenous TLR8 in primary human cells, furin/cathepsin inhibitor treatment, domain deletion mutants, subcellular fractionation Journal of immunology High 25297876
2017 Small-molecule antagonists bind to a unique site at the protein-protein interface of the TLR8 homodimer, stabilizing the preformed TLR8 dimer in its resting (inactive) state and preventing activation. Crystal structures of two TLR8-ligand complexes validated this novel binding site. X-ray crystallography of TLR8-ligand complexes, NF-κB reporter assay, cytokine measurement in human primary cells and patient specimens Nature chemical biology High 29155428
2018 Small-molecule TLR8 antagonists designed via rational structure-based drug design bind an unconventional pocket at the TLR8 protein-protein interface. X-ray crystal structures of TLR8 in complex with inhibitors confirmed the binding mode, showing the compounds sit between two TLR8 monomers preventing homodimerization. Rational structure-based design, X-ray crystallography, NF-κB reporter assay, cytokine measurement in PBMC and TLR8-transgenic mouse splenocytes Cell chemical biology High 30100350
2019 The lysosomal endoribonuclease RNase T2 is a non-redundant upstream component of TLR8-dependent RNA recognition. RNase T2 preferentially cleaves ssRNA between purine and uridine residues, generating catabolic uridine and purine-2',3'-cyclophosphate-terminated oligoribonucleotides that serve as agonistic ligands for TLR8's two distinct binding pockets. RNase T2 knockout/knockdown, reconstitution assays, biochemical characterization of RNA degradation products, TLR8 reporter assays Cell High 31778653
2010 Mouse TLR8 deficiency leads to overexpression of TLR7 on dendritic cells and hyperresponsiveness to TLR7 ligands. TLR8 functions as a negative regulator of TLR7 expression and TLR7-mediated signaling, preventing spontaneous autoimmunity. Tlr8−/− mouse model, TLR7 expression measurement, NF-κB activation assays, autoantibody measurement, histopathology The Journal of clinical investigation High 20811154
2014 TLR8 on dendritic cells (but not B cells) restrains TLR7-mediated autoimmunity, while TLR9 restrains TLR7 response specifically on B cells. Double TLR8/9-deficient mice show additive lupus-like disease. TLR8 and TLR9 act on different cell types to control TLR7. Single and double TLR8/9 knockout mice, cell-type-specific TLR7 hyperresponsiveness assays, autoantibody and disease phenotype measurement Proceedings of the National Academy of Sciences of the United States of America High 24474776
2010 TLR8 is activated in human monocytic cells following Helicobacter pylori phagocytosis. A TLR8 SNP (rs3764880:A>G; Met1Val) fine-tunes translation of the two TLR8 isoforms: TLR8 variant 2 (TLR8v2) is the prevalent functional isoform, while TLR8v1 positively regulates TLR8 function in CD16+CD14+ differentiated monocytes. siRNA knockdown, overexpression, TLR8-specific reporter assays, phagocytosis experiments with live bacteria, cytokine measurement, isoform-specific translation analysis Human mutation Medium 20652908
2007 TLR8 is expressed in neurons and axons of the mouse brain. TLR8 activation suppresses neurite outgrowth and induces neuronal apoptosis through an NF-κB-independent mechanism. TLR8 expression profiling in mouse brain development, neuronal culture assays with TLR8 ligands, NF-κB reporter assays, neurite outgrowth measurement Cell cycle Medium 18000403
2014 HIV-1 infection of human monocytes induces pro-IL-1β expression via TLR8-dependent mechanisms. TLR8 senses HIV-1-derived RNA; both HIV-1 entry, reverse transcription, and integration are required for TLR8-mediated pro-IL-1β expression. Subsequently, NLRP3 inflammasome (activated by cathepsin B and ROS) cleaves pro-IL-1β into bioactive IL-1β. TLR8 knockdown, HIV-1 infection of primary human monocytes, TLR8-specific reporter assay, HIV lifecycle inhibitors, cathepsin B inhibitor, caspase-1 assay The Journal of biological chemistry High 24939850
2015 Human TLR8 senses bacterial RNA in primary human monocyte-derived macrophages; TLR8 is unambiguously identified as the receptor for bacterial RNA using siRNA knockdown and overexpression. The TLR8-recognized sequence motif in bacterial RNA is distinct from that recognized by mouse TLR13. TLR8-dependent bacterial RNA detection is critical for monocyte activation during Streptococcus pyogenes infection. siRNA knockdown, TLR8 overexpression in macrophages, lysosomal maturation inhibitors, S. pyogenes infection, cytokine measurement Journal of immunology High 26101323
2015 Human TLR8 senses UR/URR motifs in bacterial RNA (including Sa19 23S rRNA-derived fragments) and mitochondrial 16S rRNA-derived oligoribonucleotides. TLR8 function requires UNC93B1 (lysosomal function) and acts as the human functional equivalent of mouse TLR13 for bacterial RNA sensing. TLR8 knockout THP-1 cells are refractory to these RNA stimuli. TLR8/Unc93b1 knockout THP-1 cells, TLR8 ectopic overexpression, lysosomal function inhibitors, synthetic oligoribonucleotide stimulation, NF-κB/cytokine reporter assays EMBO reports High 26545385
2009 Self-RNA complexed with the antimicrobial peptide LL37 is transported into endosomal compartments and activates TLR8 in myeloid DCs (mDCs), leading to TNF-α and IL-6 production and mDC maturation. This mechanism drives autoimmune responses in psoriasis. TLR7/TLR8 knockdown/blocking in primary DCs, confocal microscopy for LL37-RNA complex localization, cytokine ELISA, flow cytometry for DC maturation markers The Journal of experimental medicine High 19703986
2006 TLR8 activation by imidazoquinolines mediates NF-κB activation and proinflammatory cytokine production. In addition, imiquimod activates NF-κB independently of TLR7 and TLR8 through antagonism of adenosine receptors (particularly A1 and A2A subtypes), as demonstrated in Chinese hamster ovary cells expressing human adenosine receptor subtypes. TLR7/TLR8-negative cell lines, radioligand binding competition, adenylyl cyclase activity assay, CHO cells stably transfected with adenosine receptor subtypes The Journal of investigative dermatology Medium 16575388
2010 TLR8 transcriptional activity is regulated by C/EBPδ and C/EBPβ binding to three C/EBP cis-acting elements in the hTLR8 promoter. TLR8 stimulation (R848) increases TLR8 transcription via enhanced C/EBPδ binding. IFN-γ increases TLR8 transcription via STAT1 binding to IFN-γ-activated sequence (GAS) elements in the TLR8 promoter. TLR8 promoter isolation, luciferase reporter assays, chromatin immunoprecipitation (ChIP) for C/EBPδ, C/EBPβ, and STAT1 binding The Journal of biological chemistry High 20829351
2009 TLR7 and TLR8 agonists trigger different signaling pathways during human DC maturation. Both JNK and NF-κB positively regulate maturation markers and cytokines downstream of both TLR7 and TLR8. However, p38 MAPK inhibits CD40 expression and IL-12 production in TLR8-stimulated DCs (while promoting them in TLR7-stimulated DCs). The Jak/STAT pathway positively regulates CD40 and cytokines in TLR7-stimulated but negatively regulates cytokine secretion in TLR8-stimulated DCs. Selective TLR7 agonist (imiquimod) vs. TLR8 agonist (3M002), specific kinase inhibitors (p38, JNK, NF-κB, Jak/STAT), cytokine ELISA, flow cytometry for DC maturation markers Journal of leukocyte biology Medium 19164127
2019 TLR7 and TLR8 activate distinct signaling cascades in human monocytes during RNA virus infection. TLR7 specifically increases FOSL1 expression, which reduces IL-27 and TNFα production. TLR7 (but not TLR8) activation stimulates Ca2+ flux that prevents type I IFN responses. These distinct pathways correlate with different cytokine profiles for CD4+ T helper cell polarization. TLR7/TLR8-specific agonists, siRNA knockdown, signaling pathway analysis, Ca2+ flux measurement, gene expression profiling in human CD14+ monocytes infected with 6 different RNA viruses Science signaling High 31662487
2009 TLR8 is required for TNF-α overproduction in FANCC-deficient mononuclear phagocytes. TLR8 (or a TLR8-associated protein) is ubiquitinated in Fancc−/− mutant cells but not complemented cells. FANCC suppresses TLR8 activity via canonical downstream intermediates IRAK and IKKα/β, and this function is independent of FANCC's role in protecting the genome from crosslinking agents. TLR8-specific inhibitory sequences, FANCC-deficient THP-1 cells and Fancc−/− macrophages, TLR8 agonist stimulation, ubiquitination proteomics, FANCC point mutant complementation Blood Medium 19850743
2016 DCIR (an ITIM-containing C-type lectin receptor) is endocytosed via clathrin-dependent internalization into endo-/lysosomal compartments including LAMP-1+ lysosomes. DCIR triggering specifically inhibits TLR8-mediated IL-12 and TNF-α production but does not affect TLR2-, TLR3-, or TLR4-induced cytokine production, demonstrating CLR/TLR8 crosstalk. Confocal microscopy with endosomal markers, clathrin inhibitor, DCIR-specific mAb triggering, cytokine ELISA, co-stimulatory molecule flow cytometry Journal of leukocyte biology Medium 19028959
2016 TLR8 couples with SOCS-1 (suppressor of cytokine signaling-1) in mice; SOCS-1 directly associates with TLR8 but not TLR7. This TLR8-SOCS-1 interaction inhibits TLR7-mediated antiviral immunity (including ISG-56 expression and IFN responses) during West Nile virus infection. Tlr8−/− mice show increased TLR7 and ISG-56 expression and are resistant to WNV infection. TLR8−/− mice, SOCS-1 co-immunoprecipitation with TLR7 and TLR8, siRNA knockdown of SOCS-1, WNV infection model, gene expression analysis Journal of immunology Medium 27798161
2018 TLR8 activation in neurons promotes dendritic pruning via MyD88 signaling and specifically involves MAPK signaling. TLR8 is more critical for dendritic arborization at late developmental stages in vivo. Unlike TLR7 and TLR3, TLR8 activation does not control axonal growth. In vitro neuronal cultures, in utero electroporation, transcriptomic profiling, MAPK pathway inhibitors, TLR-specific agonists, TLR8 knockdown The Journal of cell biology Medium 29777026
2018 TLR8 senses bacterial RNA from live bacteria (but not dead bacteria) as a distinguishing viability signal, inducing a specific cytokine profile in APCs that promotes follicular helper T (TFH) cell differentiation and antibody responses. A hypermorphic TLR8 polymorphism is associated with protective BCG vaccine immunity in humans. Live vs. heat-killed bacterial comparison, TLR8-specific agonists, human and porcine APC stimulation, TFH differentiation assays, pig live vaccination model, human BCG cohort analysis Nature immunology High 29556002
2018 TLR8 in dorsal root ganglion neurons localizes to endosomes and lysosomes and mediates ERK activation, inflammatory mediator production, and neuronal hyperexcitability after spinal nerve ligation. miR-21 is increased in DRG neurons after nerve injury and serves as an endogenous TLR8 ligand that drives neuropathic pain hypersensitivity. Tlr8−/− mice, intrathecal/intradermal TLR8 agonist injection, miR-21 inhibition, ERK phosphorylation assays, electrophysiology, confocal microscopy for TLR8 subcellular localization The Journal of experimental medicine High 30455267
2020 TLR8 (but not TLR7 or TLR9) in CD4+ T cells senses endosomal HIV-1 ssRNA, inducing cytokine secretion, upregulating activation markers, promoting Th1/Th17 differentiation, enhancing HIV-1 replication, and potentiating reversal of latency in patient-derived T cells. Synthetic TLR-specific ligands, TLR-specific blocking, primary CD4+ T cell assays, HIV-1 infection of patient-derived cells, latency reversal assay, cytokine/activation marker measurement Nature communications High 31919342
2022 CXCL4 costimulation synergizes with TLR8 to activate TBK1 and IKKε, repurposing these kinases to couple with IRF5 (rather than IRF3) for an inflammatory response. This synergy activates the NLRP3 inflammasome, induces de novo enhancers associated with inflammatory genes, and selectively amplifies inflammatory gene transcription and IL-1β production while partially attenuating the IFN response. Phosphoproteomics, ChIP-seq/ATAC-seq for chromatin remodeling, kinase inhibitors, IRF5 knockdown, NLRP3 inflammasome assays in human monocytes/macrophages Nature communications High 35701499
2016 TLR8 agonism activates the NLRP3 inflammasome in monocytes, mediating release of mature IL-1β and IL-18. TLR8 primes monocytes for pro-IL-1β, pro-IL-18, and caspase-1 production, while also activating the NLRP3 complex. Caspase-1 inhibition blocks inflammasome activation but not other TLR8-induced mediators (e.g., TNFα). Caspase-1 inhibitor, NLRP3 inhibitors, cytokine ELISA (mature IL-1β, IL-18), in vivo cynomolgus monkey pharmacodynamics PloS one Medium 26928328
2022 Microbial small RNAs (msRNA) enriched on LDL activate macrophage TLR8, driving pro-inflammatory macrophage polarization. Competitive TLR8 antagonism with locked nucleic acids prevented native LDL-induced macrophage polarization in vitro and reorganized lesion macrophage phenotypes in vivo, reducing atherosclerosis disease burden. LDL reconstitution (with/without msRNA cargo), TLR8 antagonist, single-cell RNA sequencing, mouse atherosclerosis models Nature cell biology High 36474072
2021 Gain-of-function variants in TLR8 cause a novel childhood-onset inborn error of immunity. All identified variants confer constitutive or enhanced TLR8 activity, leading to proinflammatory T cell activation, elevated serum cytokines, and impaired B cell maturation. iPSC-derived myeloid cells from patients showed increased TLR8 responsiveness. Patient-derived iPSC myeloid differentiation, in vitro TLR8 activity assays in transfected cell lines and patient primary cells, immune phenotyping Blood Medium 33512449
2022 TLR8 p.G572V mutation causes impaired TLR8 protein stability, cross-reactivity to TLR7 ligands, and reduced ability of TLR8 to attenuate TLR7 signaling. This imbalance toward TLR7-dependent signaling leads to NF-κB activation and elevated IL-1β, IL-6, and TNFα production. In vitro transfection assays with mutant TLR8, primary cell assays, NF-κB reporter, cytokine measurement, patient primary cells American journal of hematology Medium 34981838
2023 TLR8 escapes X chromosome inactivation (XCI) in human CD14+ monocytes and CD4+ T cells. Both TLR7 and TLR8 genes can be simultaneously expressed from the active X chromosome, occurring more frequently in women and Klinefelter syndrome men than in euploid men (sevenfold difference in frequency). TLR8 protein expression is significantly higher in female mononuclear blood cells than in male cells. RNA FISH for primary transcripts relative to X chromosome territories in primary immune cells, Western blot and flow cytometry for TLR8 protein expression across sex groups Biology of sex differences Medium 37723501
2019 TLR8 is a dominating sensor of multiple pyogenic bacteria (S. aureus, GBS, S. pneumoniae, P. aeruginosa) in human primary monocytes, largely responsible for IL-1β and IL-12p70 production. Cell surface TLR activation (TLR2, TLR4, TLR5) attenuates TLR8-IRF5 signaling by modifying/sequestering IRAK-1, which is required for TLR8-IRF5 pathway activation. IRAK-1 silencing reduces TLR8-driven IFNβ and TNF. Selective TLR8 chemical antagonist, siRNA knockdown of IRAK-1, TLR agonist combinations, immunoblotting for IRAK-1 modifications, cytokine ELISA in primary human monocytes Frontiers in immunology High 31214180
2020 TLR8 inhibition in the trigeminal ganglion (TG) attenuates trigeminal neuropathic pain. TLR8 activation in TG neurons induces ERK and p38 MAPK activation and pro-inflammatory cytokine production. Intra-TG injection of TLR8 agonist VTX-2337 induces pain hypersensitivity and increases intracellular Ca2+ concentration in TG neurons. Tlr8 knockdown and conditional deletion in TG, ERK/p38 phosphorylation assays, cytokine measurement, Ca2+ imaging, behavioral pain assays Neuroscience bulletin Medium 33355900
2014 TLR8 activation promotes AML cell differentiation and growth inhibition in a TLR8/MyD88/p38-dependent manner, establishing a direct anti-leukemic role for TLR8 signaling independent of immunomodulation. TLR8 agonist (R848) stimulation, MyD88 and p38 pathway inhibitors, TLR8 overexpression, in vivo xenograft model Leukemia Medium 25283842
2024 TLR8 is expressed in the hepatic myeloid compartment (Kupffer cells). TLR8 agonism (selgantolimod) activates Kupffer cells and induces IL-6 secretion, which indirectly impairs HBV entry into hepatocytes by downregulating NTCP (sodium taurocholate cotransporting polypeptide). Co-treatment with an anti-IL-6 neutralizing antibody reverses the HBV entry inhibition. Single-cell RNA-seq of human liver, Kupffer cell isolation and TLR8 agonist treatment, SLGN-conditioned media transfer to hepatocytes, HBV infection quantification, anti-IL-6 neutralization, RNA-seq of Kupffer cells and hepatocytes Gut High 38697771

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 971 20832340
2009 Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. The Journal of experimental medicine 581 19703986
2000 Cloning and characterization of a sub-family of human toll-like receptors: hTLR7, hTLR8 and hTLR9. European cytokine network 322 11022120
2008 Identification of RNA sequence motifs stimulating sequence-specific TLR8-dependent immune responses. Journal of immunology (Baltimore, Md. : 1950) 254 18322178
2008 TLR7 and TLR8 as targets in cancer therapy. Oncogene 245 18176600
2012 TLR8: the forgotten relative revindicated. Cellular & molecular immunology 208 23085951
2010 Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance. The Journal of clinical investigation 180 20237413
2008 The use of TLR7 and TLR8 ligands for the enhancement of cancer immunotherapy. The oncologist 177 18701762
2019 TLR8 Is a Sensor of RNase T2 Degradation Products. Cell 163 31778653
2010 TLR8 deficiency leads to autoimmunity in mice. The Journal of clinical investigation 160 20811154
2013 RNA recognition by human TLR8 can lead to autoimmune inflammation. The Journal of experimental medicine 157 24277153
2014 HIV-1 infection induces interleukin-1β production via TLR8 protein-dependent and NLRP3 inflammasome mechanisms in human monocytes. The Journal of biological chemistry 142 24939850
2014 TLR8 signaling enhances tumor immunity by preventing tumor-induced T-cell senescence. EMBO molecular medicine 141 25231413
2005 Activation of innate defense against a paramyxovirus is mediated by RIG-I and TLR7 and TLR8 in a cell-type-specific manner. Journal of virology 141 16188996
2019 TLR7 and TLR8 activate distinct pathways in monocytes during RNA virus infection. Science signaling 139 31662487
2006 The small antitumoral immune response modifier imiquimod interacts with adenosine receptor signaling in a TLR7- and TLR8-independent fashion. The Journal of investigative dermatology 135 16575388
2008 Association analysis identifies TLR7 and TLR8 as novel risk genes in asthma and related disorders. Thorax 124 18682521
2018 Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses. Nature immunology 122 29556002
2018 TLR8 and its endogenous ligand miR-21 contribute to neuropathic pain in murine DRG. The Journal of experimental medicine 122 30455267
2011 Phagosomal signaling by Borrelia burgdorferi in human monocytes involves Toll-like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN-beta. Proceedings of the National Academy of Sciences of the United States of America 116 21321205
2008 DCIR is endocytosed into human dendritic cells and inhibits TLR8-mediated cytokine production. Journal of leukocyte biology 114 19028959
2017 Small-molecule inhibition of TLR8 through stabilization of its resting state. Nature chemical biology 112 29155428
2020 TLR7 and TLR8 Differentially Activate the IRF and NF-κB Pathways in Specific Cell Types to Promote Inflammation. ImmunoHorizons 102 32086319
2014 TLR8 on dendritic cells and TLR9 on B cells restrain TLR7-mediated spontaneous autoimmunity in C57BL/6 mice. Proceedings of the National Academy of Sciences of the United States of America 102 24474776
2009 TLR7 and TLR8 agonists trigger different signaling pathways for human dendritic cell maturation. Journal of leukocyte biology 95 19164127
2009 Identification and characterization of TLR8 and MyD88 homologs in Atlantic salmon (Salmo salar). Developmental and comparative immunology 95 19422846
2009 A five-amino-acid motif in the undefined region of the TLR8 ectodomain is required for species-specific ligand recognition. Molecular immunology 91 20004021
2020 Trial Watch: experimental TLR7/TLR8 agonists for oncological indications. Oncoimmunology 89 32934889
2009 Human dendritic cells stimulated via TLR7 and/or TLR8 induce the sequential production of Il-10, IFN-gamma, and IL-17A by naive CD4+ T cells. Journal of immunology (Baltimore, Md. : 1950) 89 19265114
2015 Human TLR8 senses UR/URR motifs in bacterial and mitochondrial RNA. EMBO reports 84 26545385
2006 TLR8-mediated NF-kappaB and JNK activation are TAK1-independent and MEKK3-dependent. The Journal of biological chemistry 84 16737960
2015 TLR7 and TLR8 expression increases tumor cell proliferation and promotes chemoresistance in human pancreatic cancer. International journal of oncology 79 26134824
2021 Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function. Blood 78 33512449
2007 TLR8: an innate immune receptor in brain, neurons and axons. Cell cycle (Georgetown, Tex.) 78 18000403
2016 IFNα enhances the production of IL-6 by human neutrophils activated via TLR8. Scientific reports 76 26790609
2006 Oligodeoxynucleotides differentially modulate activation of TLR7 and TLR8 by imidazoquinolines. Journal of immunology (Baltimore, Md. : 1950) 74 17114492
2008 RNA recognition via TLR7 and TLR8. Handbook of experimental pharmacology 73 18071655
2020 Sensing of HIV-1 by TLR8 activates human T cells and reverses latency. Nature communications 71 31919342
2015 TLR8 Senses Bacterial RNA in Human Monocytes and Plays a Nonredundant Role for Recognition of Streptococcus pyogenes. Journal of immunology (Baltimore, Md. : 1950) 71 26101323
2014 Endosomal localization of TLR8 confers distinctive proteolytic processing on human myeloid cells. Journal of immunology (Baltimore, Md. : 1950) 70 25297876
2011 TLR7 and TLR8 gene variations and susceptibility to hepatitis C virus infection. PloS one 67 22022576
2010 Toll-like receptor (TLR) 7 and TLR8 expression on CD133+ cells in colorectal cancer points to a specific role for inflammation-induced TLRs in tumourigenesis and tumour progression. European journal of cancer (Oxford, England : 1990) 66 20728343
2010 Genetic modulation of TLR8 response following bacterial phagocytosis. Human mutation 64 20652908
2009 TLR8-dependent TNF-(alpha) overexpression in Fanconi anemia group C cells. Blood 64 19850743
2013 The ultra-potent and selective TLR8 agonist VTX-294 activates human newborn and adult leukocytes. PloS one 60 23483986
2013 TLR8 stimulation enhances cetuximab-mediated natural killer cell lysis of head and neck cancer cells and dendritic cell cross-priming of EGFR-specific CD8+ T cells. Cancer immunology, immunotherapy : CII 60 23685782
2021 Glucose metabolism characteristics and TLR8-mediated metabolic control of CD4+ Treg cells in ovarian cancer cells microenvironment. Cell death & disease 59 33414414
2018 Endosomal TLR3, TLR7, and TLR8 control neuronal morphology through different transcriptional programs. The Journal of cell biology 59 29777026
2019 Human Toll-like Receptor 8 (TLR8) Is an Important Sensor of Pyogenic Bacteria, and Is Attenuated by Cell Surface TLR Signaling. Frontiers in immunology 57 31214180
2009 TLR7 and TLR8 ligands and antiphospholipid antibodies show synergistic effects on the induction of IL-1beta and caspase-1 in monocytes and dendritic cells. Immunobiology 55 19249118
2016 Coordinated Activation of Toll-Like Receptor8 (TLR8) and NLRP3 by the TLR8 Agonist, VTX-2337, Ignites Tumoricidal Natural Killer Cell Activity. PloS one 54 26928328
2011 UNC93B1 physically associates with human TLR8 and regulates TLR8-mediated signaling. PloS one 54 22164301
2014 The role of TLR8 signaling in acute myeloid leukemia differentiation. Leukemia 53 25283842
2018 Small-Molecule TLR8 Antagonists via Structure-Based Rational Design. Cell chemical biology 48 30100350
2016 Estrogen-regulated STAT1 activation promotes TLR8 expression to facilitate signaling via microRNA-21 in systemic lupus erythematosus. Clinical immunology (Orlando, Fla.) 48 28039018
2008 Porcine TLR8 and TLR7 are both activated by a selective TLR7 ligand, imiquimod. Molecular immunology 48 18439678
2011 VTX-1463, a novel TLR8 agonist for the treatment of allergic rhinitis. Expert opinion on investigational drugs 47 21548830
2015 Structure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity. Journal of medicinal chemistry 45 26351878
2022 Safety and efficacy of the oral TLR8 agonist selgantolimod in individuals with chronic hepatitis B under viral suppression. Journal of hepatology 44 38133554
2016 Identification and expression analysis of toll-like receptor genes (TLR8 and TLR9) in mucosal tissues of turbot (Scophthalmus maximus L.) following bacterial challenge. Fish & shellfish immunology 44 27633670
2023 TLR8 escapes X chromosome inactivation in human monocytes and CD4+ T cells. Biology of sex differences 43 37723501
2013 1,25-Dihydroxyvitamin D3 suppresses TLR8 expression and TLR8-mediated inflammatory responses in monocytes in vitro and experimental autoimmune encephalomyelitis in vivo. PloS one 41 23516559
2011 The TLR7/8 ligand resiquimod targets monocyte-derived dendritic cell differentiation via TLR8 and augments functional dendritic cell generation. Cellular immunology 41 21889130
2019 Human neutrophils activated via TLR8 promote Th17 polarization through IL-23. Journal of leukocyte biology 40 30817049
2014 Functional polymorphisms of TLR8 are associated with hepatitis C virus infection. Immunology 40 24205871
2020 LncRNA TLR8-AS1 promotes metastasis and chemoresistance of ovarian cancer through enhancing TLR8 mRNA stability. Biochemical and biophysical research communications 38 32278547
2022 CXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes. Nature communications 36 35701499
2009 High-frequency haplotypes in the X chromosome locus TLR8 are associated with both CD and UC in females. Inflammatory bowel diseases 34 18942751
2009 Characterization of equine and other vertebrate TLR3, TLR7, and TLR8 genes. Immunogenetics 34 19568743
2021 Safety, Pharmacokinetics, and Pharmacodynamics of the Oral TLR8 Agonist Selgantolimod in Chronic Hepatitis B. Hepatology (Baltimore, Md.) 33 33704806
2021 MicroRNA-21 regulate the cell apoptosis and cell proliferation of polycystic ovary syndrome (PCOS) granulosa cells through target toll like receptor TLR8. Bioengineered 33 34516355
2010 C/EBP{delta} and STAT-1 are required for TLR8 transcriptional activity. The Journal of biological chemistry 31 20829351
2022 LDL delivery of microbial small RNAs drives atherosclerosis through macrophage TLR8. Nature cell biology 30 36474072
2019 Human TLR8 Senses RNA From Plasmodium falciparum-Infected Red Blood Cells Which Is Uniquely Required for the IFN-γ Response in NK Cells. Frontiers in immunology 30 30972055
2017 Identification of High-Potency Human TLR8 and Dual TLR7/TLR8 Agonists in Pyrimidine-2,4-diamines. Journal of medicinal chemistry 30 28146629
2014 Viral single stranded RNA induces a trophoblast pro-inflammatory and antiviral response in a TLR8-dependent and -independent manner. Biology of reproduction 30 25429091
2013 Inosine-mediated modulation of RNA sensing by Toll-like receptor 7 (TLR7) and TLR8. Journal of virology 30 24227841
2019 p53-responsive TLR8 SNP enhances human innate immune response to respiratory syncytial virus. The Journal of clinical investigation 29 31430261
2016 Functional polymorphisms of the TLR7 and TLR8 genes contribute to Mycobacterium tuberculosis infection. Tuberculosis (Edinburgh, Scotland) 28 27156628
2019 The Bacterial Product Violacein Exerts an Immunostimulatory Effect Via TLR8. Scientific reports 26 31541142
2016 Increased adipose tissue expression of TLR8 in obese individuals with or without type-2 diabetes: significance in metabolic inflammation. Journal of inflammation (London, England) 26 27980459
2022 TLR8/TLR7 dysregulation due to a novel TLR8 mutation causes severe autoimmune hemolytic anemia and autoinflammation in identical twins. American journal of hematology 25 34981838
2009 TLR8-mediated activation of human monocytes inhibits TL1A expression. European journal of immunology 25 19637197
2017 Impaired expression and function of TLR8 in chronic HBV infection and its association with treatment responses during peg-IFN-α-2a antiviral therapy. Clinics and research in hepatology and gastroenterology 24 28236535
2017 TLR8 ligation induces apoptosis of monocytic myeloid-derived suppressor cells. Journal of leukocyte biology 24 29345064
2015 A single naturally occurring 2'-O-methylation converts a TLR7- and TLR8-activating RNA into a TLR8-specific ligand. PloS one 24 25785446
2020 Rationally Designed Small-Molecule Inhibitors Targeting an Unconventional Pocket on the TLR8 Protein-Protein Interface. Journal of medicinal chemistry 23 32233366
2017 Molecular cloning and expression analysis of toll-like receptor genes (TLR7, TLR8 and TLR9) of golden pompano (Trachinotus ovatus). Fish & shellfish immunology 23 28232281
2016 TLR8 Couples SOCS-1 and Restrains TLR7-Mediated Antiviral Immunity, Exacerbating West Nile Virus Infection in Mice. Journal of immunology (Baltimore, Md. : 1950) 23 27798161
2022 SARS-CoV-2-Associated ssRNAs Activate Human Neutrophils in a TLR8-Dependent Fashion. Cells 22 36497044
2021 Follicular Helper T (TFH) Cell Targeting by TLR8 Signaling For Improving HBsAg-Specific B Cell Response In Chronic Hepatitis B Patients. Frontiers in immunology 22 34512670
2013 Identification, expression profiling of a grass carp TLR8 and its inhibition leading to the resistance to reovirus in CIK cells. Developmental and comparative immunology 22 23632252
2021 Interaction of TLR4 and TLR8 in the Innate Immune Response against Mycobacterium Tuberculosis. International journal of molecular sciences 21 33557133
2020 TLR8 in the Trigeminal Ganglion Contributes to the Maintenance of Trigeminal Neuropathic Pain in Mice. Neuroscience bulletin 21 33355900
2015 TLR8 gene polymorphism and association in bacterial load in southern Punjab of Pakistan: an association study with pulmonary tuberculosis. International journal of immunogenetics 21 25572425
2011 Dual or triple activation of TLR7, TLR8, and/or TLR9 by single-stranded oligoribonucleotides. Nucleic acid therapeutics 21 22196370
2010 Characterization of ovine TLR7 and TLR8 protein coding regions, detection of mutations and Maedi Visna virus infection. Veterinary immunology and immunopathology 21 20638136
2009 TLR8-driven IL-12-dependent reciprocal and synergistic activation of NK cells and monocytes by immunostimulatory RNA. Journal of immunotherapy (Hagerstown, Md. : 1997) 20 19242374
2016 Imiquimod induces ER stress and Ca(2+) influx independently of TLR7 and TLR8. Biochemical and biophysical research communications 19 27003259
2024 TLR8 agonist selgantolimod regulates Kupffer cell differentiation status and impairs HBV entry into hepatocytes via an IL-6-dependent mechanism. Gut 18 38697771

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