Affinage

TLR7

Toll-like receptor 7 · UniProt Q9NYK1

Length
1049 aa
Mass
120.9 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 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

TLR7 is an endosomal single-stranded RNA sensor of innate immunity that signals through MyD88 to drive type I interferon and inflammatory cytokine production (PMID:14976261). Rather than recognizing intact RNA, TLR7 detects degradation products generated within the endolysosome: lysosomal RNase T2 cleaves RNA, and the exonucleases PLD3/PLD4 release guanosine-derived 2',3'-cGMP for one binding pocket and pyrimidine-rich fragments for a second pocket, so that both ligand classes are produced cooperatively from RNA processing (PMID:38697119, PMID:34161582). Consistent with this, TLR7 senses free guanosine, deoxyguanosine and oxidized guanosine nucleosides, with oligoribonucleotide co-presentation strengthening nucleoside binding (PMID:26489884, PMID:31608988), and the nucleoside salvage enzyme PNP limits ligand availability by clearing (deoxy)guanosine (PMID:35653193). Structurally TLR7 cycles between open (inactive) and closed (active) conformations and exists as a ligand-independent oligomer, with antagonists stabilizing the open state (PMID:33060576, PMID:26784926). Downstream of receptor engagement TLR7 recruits MyD88 to activate NF-κB, MAPK/JNK and Jak/STAT cascades (PMID:25848864, PMID:19164127), and engages the SLC15A4-associated adaptor TASL through its pLxIS motif to activate IRF5 specifically along the IRF branch (PMID:32433612). TLR7 abundance, localization and signaling threshold are set by trafficking machinery: UNC93B1 recruits syntenin-1 to sort TLR7 into multivesicular bodies and terminate signaling (PMID:31546246) and interacts with the BORC–Arl8b axis to control endosomal receptor turnover (PMID:38207015), while SHP2-mediated dephosphorylation of TLR7-Tyr1024 promotes Golgi-to-endosome trafficking and ubiquitination (PMID:34936223). Excess TLR7 dosage or activity drives B cell-intrinsic autoimmunity: gain-of-function variants (Y264H; dimerization-interface F507S/L528I) cause lupus and neuroinflammatory disease in a MyD88-dependent manner (PMID:35477763, PMID:38324161), escape from X-chromosome inactivation raises biallelic TLR7 expression and amplifies B cell responses (PMID:29374079), and UNC93B1 mutations that disrupt TLR7 trafficking cause childhood-onset lupus (PMID:38207015, PMID:38207055). Chronic TLR7 signaling also specifies pathogenic monocyte fates via IRF5 (PMID:30630901) and contributes to histiocytosis, psoriasis, emphysema, demyelination, and breast cancer metastasis through tissue-specific effector pathways (PMID:39112700, PMID:37462944, PMID:37963864, PMID:39607927).

Mechanistic history

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

    Established the founding identity of TLR7 as an endosomal ssRNA sensor coupled to MyD88, defining both ligand class and signaling adaptor.

    Evidence TLR7- and MyD88-deficient mice with viral and synthetic ssRNA in endosomal recognition assays

    PMID:14976261

    Open questions at the time
    • Did not define the precise molecular feature of RNA recognized
    • Did not resolve how RNA reaches the endosomal receptor
  2. 2008 Medium

    Showed TLR7 ectodomain residues distinguish RNA versus imidazoquinoline ligands and that ligand class dictates distinct phosphorylation and transcriptional outputs, hinting at dual recognition modes.

    Evidence Ectodomain mutagenesis and proteome/genome-wide analysis in primary human monocyte-derived DCs

    PMID:24813206

    Open questions at the time
    • Binding sites inferred from mutagenesis, not direct structure
    • Mechanistic link between ligand class and downstream output not fully resolved
  3. 2015 High

    Identified guanosine-family nucleosides as endogenous TLR7 ligands whose binding is enhanced by oligoribonucleotides, reframing TLR7 as a sensor of RNA degradation products rather than intact RNA.

    Evidence ITC binding assays plus cytokine readouts in mouse and human cells with Unc93b1 controls

    PMID:26489884

    Open questions at the time
    • Did not establish the enzymatic source of nucleoside ligands
    • Two-pocket structural basis not yet defined
  4. 2015 High

    Demonstrated functional cell-surface TLR7 in addition to endolysosomal pools, expanding the receptor's localization and showing surface receptor can be targeted therapeutically.

    Evidence Anti-TLR7 antibody internalization, fractionation/immunofluorescence and in vivo treatment of Unc93b1 D34A autoimmune mice

    PMID:25648980

    Open questions at the time
    • Relative contribution of surface versus endosomal TLR7 to physiologic signaling unclear
    • Trafficking route between surface and endosome not defined here
  5. 2019 High

    Established that deoxyguanosine activates TLR7 independently of supplied ssRNA but still requires MyD88 and endosomal maturation, confirming nucleosides as bona fide RNA-independent agonists.

    Evidence Cytokine assays in TLR7-/- and MyD88-/- macrophages/pDCs with bafilomycin A1 blockade

    PMID:31608988

    Open questions at the time
    • Did not show which pocket dG occupies
    • Source of endogenous dG in vivo not addressed
  6. 2019 High

    Defined UNC93B1–syntenin-1 sorting into multivesicular bodies as the mechanism that selectively terminates TLR7 signaling, linking receptor trafficking to autoimmunity.

    Evidence Reciprocal Co-IP, phosphorylation-dependent binding, exosome fractionation and UNC93B1 mutant autoimmune mice

    PMID:31546246

    Open questions at the time
    • Kinase phosphorylating UNC93B1 not identified
    • TLR9 selectivity mechanism not fully explained
  7. 2020 High

    Provided the structural framework of TLR7 conformational equilibrium and a defined antagonist pocket, enabling rational stabilization of the inactive open state.

    Evidence X-ray crystallography, cryo-EM and structure-guided antagonist with in vivo autoimmunity protection

    PMID:33060576

    Open questions at the time
    • Did not capture full active dimer with both physiologic ligands
    • Conformational dynamics during signaling not resolved in cells
  8. 2020 High

    Identified TASL as the SLC15A4-bound, pLxIS-motif adaptor that specifically couples endosomal TLRs to IRF5, defining the IRF branch of TLR7 signaling distinct from NF-κB/MAPK.

    Evidence TASL knockout, pLxIS mutagenesis and pathway dissection in human immune cells

    PMID:32433612

    Open questions at the time
    • Structural basis of TASL–IRF5 engagement not resolved here
    • How signal selectivity between TLR7/8/9 is achieved unclear
  9. 2021 Medium

    Linked endosomal RNA processing to TLR7 activation by showing RNase T2 catalytic activity is required to generate TLR7-activating ligands, oppositely regulating TLR3.

    Evidence RNase T2-deficient macrophages with catalytic mutant rescue and in vitro degradation assays

    PMID:34161582

    Open questions at the time
    • Did not define the exact RNase T2 product engaging TLR7
    • Single lab; ligand chemistry resolved only later
  10. 2021 High

    Defined SHP2-mediated dephosphorylation of TLR7-Tyr1024 as a post-translational switch promoting Golgi-to-endosome trafficking and ubiquitination, tuning inflammatory output.

    Evidence SHP2 inhibitor, conditional SHP2 KO, TLR7 Tyr1024 point-mutant knock-in mice and fractionation

    PMID:34936223

    Open questions at the time
    • Kinase adding the Tyr1024 phosphate not identified
    • Generalizability beyond macrophage skin inflammation untested here
  11. 2022 High

    Proved a single human gain-of-function variant (Y264H) increasing nucleoside sensing is sufficient to cause lupus and that pathology is entirely MyD88-dependent and B cell-intrinsic.

    Evidence Human de novo variant, knock-in mouse, MyD88-deficient rescue epistasis and B cell assays

    PMID:35477763

    Open questions at the time
    • Did not map the contribution of non-B-cell TLR7
    • Structural effect of Y264H on the binding pocket not directly visualized
  12. 2022 Medium

    Showed PNP controls TLR7 by limiting intracellular guanosine ligand levels, identifying nucleoside metabolism as a tunable upstream determinant of TLR7-driven autoimmunity.

    Evidence PNP genetic/pharmacologic inactivation with TLR7-dependent cytokine and germinal center assays

    PMID:35653193

    Open questions at the time
    • Single lab
    • Quantitative relationship between PNP activity and TLR7 threshold not defined
  13. 2024 High

    Resolved the enzymatic two-step generation of both TLR7 ligand classes, showing RNase T2 then PLD3/PLD4 homodimers produce 2',3'-cGMP for pocket 1 and pyrimidine fragments for pocket 2.

    Evidence Reconstitution biochemistry, PLD homodimer crystallography/cryo-EM and cell-based loss-of-function

    PMID:38697119

    Open questions at the time
    • In vivo stoichiometry of the two pockets during physiologic signaling unclear
    • How disease PLD mutants alter human TLR7 thresholds quantitatively not defined
  14. 2024 High

    Established the BORC–Arl8b–UNC93B1 axis as a controller of endosomal TLR7 turnover, with a patient UNC93B1 mutation causing TLR7 accumulation and childhood-onset lupus.

    Evidence UNC93B1–Arl8b interaction studies, patient-derived mutant analysis and endosomal TLR7 quantification

    PMID:38207015

    Open questions at the time
    • Full BORC subunit requirements not dissected
    • How turnover defect translates to specific B cell autoimmunity not detailed
  15. 2024 High

    Showed UNC93B1 missense variants confer selective TLR7 hyperactivation via protein instability and altered TLR7 interaction, demonstrating UNC93B1 controls TLR7 subtype-specific recognition.

    Evidence Patient cells and UNC93B1-variant mouse macrophages with TLR7/8/9 agonist and interaction assays

    PMID:38207055

    Open questions at the time
    • Mechanism of TLR7-versus-TLR9 selectivity at residue level incomplete
    • Structural consequence of variants not solved
  16. 2024 Medium

    Identified dimerization-interface gain-of-function variants (F507S, L528I) that enhance TLR7 homodimerization to cause systemic and neuroinflammatory disease, extending the GOF allelic series beyond ligand sensing.

    Evidence Human patient variants, structural modeling and functional signaling in patient cells

    PMID:38324161

    Open questions at the time
    • Dimerization enhancement is partly computational
    • Direct structural confirmation of altered dimer interface lacking
  17. 2024 High

    Revealed a non-canonical TLR7 role in cancer: tumor-cell TLR7 senses extracellular ssRNA released by substance-P-killed cells to drive a prometastatic program, extending TLR7 beyond immune cells.

    Evidence 3D co-cultures, TLR7-deficient cancer cells, TACR1 antagonism and in vivo mammary tumor models

    PMID:39112700

    Open questions at the time
    • Adaptor usage for the prometastatic program not defined
    • Whether canonical MyD88/IRF pathways are involved unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the two ligand pockets, conformational equilibrium, trafficking checkpoints and adaptor choice (MyD88/NF-κB vs TASL/IRF5) are integrated to set quantitative signaling thresholds across distinct cell types and diseases remains unresolved.
  • No unified structural model of the active TLR7 dimer bound to both physiologic ligands
  • Cell-type-specific determinants of NF-κB versus IRF5 branch selection undefined
  • Mechanism distinguishing protective immunity from pathogenic autoimmunity at a single threshold unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 4 GO:0060089 molecular transducer activity 3 GO:0001618 virus receptor activity 2
Localization
GO:0005768 endosome 4 GO:0005764 lysosome 3 GO:0005794 Golgi apparatus 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4
Partners
MYD88SHP2SLC15A4TASLTREML4UNC93B1

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 TLR7 recognizes single-stranded RNA (ssRNA) in endosomal compartments and signals through MyD88 to induce type I IFN and inflammatory cytokine production; ssRNA of non-viral origin also activates TLR7, identifying ssRNA as a TLR7 ligand. TLR7-deficient mice, MyD88-deficient mice, endosomal recognition assays with influenza genomic RNA and synthetic ssRNA Science High 14976261
2008 TLR7 and TLR8 ectodomains sense RNA oligoribonucleotides (ORN) and imidazoquinolines through overlapping but non-identical recognition sites; RNA ORN versus imidazoquinoline binding produces ligand-specific differential phosphorylation and distinct transcriptional responses, suggesting TLR7 can signal in two different 'modes' depending on ligand class. Proteome- and genome-wide analysis, mutagenesis of ectodomain residues, primary human monocyte-derived DCs Journal of immunology Medium 24813206
2015 TLR7 senses guanosine (G), 2'-deoxyguanosine (dG), 7-methylguanosine, 8-hydroxyguanosine (8-OHG), and 8-hydroxydeoxyguanosine (8-OHdG) as endogenous small-molecule ligands when co-presented with an oligoribonucleotide (ORN); ORN strengthens TLR7 interaction with G/dG as measured by isothermal titration calorimetry. Cytokine production assays in mouse and human immune cells, isothermal titration calorimetry (ITC) binding assay, Unc93b1-mutant macrophages International immunology High 26489884
2019 Deoxyguanosine (dG) activates TLR7 independently of concurrent ssRNA provision; this signaling requires TLR7 and its adaptor MyD88 and depends on endosomal maturation, establishing dG as an RNA-independent TLR7 agonist. Cytokine production in TLR7-/- and MyD88-/- murine macrophages and pDCs, bafilomycin A1 endosomal acidification blockade, human PBMCs European journal of immunology High 31608988
2024 Lysosomal endonuclease RNase T2 generates guanosine 2',3'-cyclic monophosphate-terminated RNA fragments; PLD3/PLD4 exonucleases then release 2',3'-cGMP to engage TLR7 pocket 1 and generate pyrimidine-rich RNA fragments for TLR7 pocket 2, cooperatively producing both classes of TLR7 ligands. PLD enzymes form homodimers with two ligand-binding sites required for activity; disease-associated PLD mutants fail to form stable dimers. Biochemical assays, structural studies, loss-of-function studies in cell lines and primary cells, crystallography/cryo-EM of PLD homodimers Immunity High 38697119
2020 TLR7 structural analysis by combined crystallography and cryo-EM reveals an equilibrium between open and closed receptor conformations; TLR7-specific antagonists bind a defined pocket and stabilize the open (inactive) conformation, providing the structural basis for TLR7 antagonism. X-ray crystallography, cryo-electron microscopy, structure-guided antagonist development, in vivo autoimmunity protection assay Nature communications High 33060576
2022 A gain-of-function missense variant TLR7Y264H selectively increases TLR7 sensing of guanosine and 2',3'-cGMP and is sufficient to cause lupus when introduced into mice; downstream pathogenesis requires MyD88 (deficiency of MyD88 rescued all phenotypes), and TLR7Y264H drives cell-intrinsic aberrant survival of BCR-activated B cells and accumulation of CD11c+ age-associated B cells. Human genetic identification of de novo variant, knock-in mouse model, MyD88-deficient rescue epistasis, B cell functional assays Nature High 35477763
2019 UNC93B1 specifically limits TLR7 (but not TLR9) signaling by recruiting syntenin-1, which facilitates sorting of TLR7 into intraluminal vesicles of multivesicular bodies to terminate signaling; this recruitment requires phosphorylation of UNC93B1. Mutations in UNC93B1 that disrupt syntenin-1 binding cause enhanced TLR7 signaling and TLR7-dependent autoimmunity in mice. Co-immunoprecipitation, UNC93B1 mutant mice, exosome fractionation, phosphorylation-dependent binding assays, in vivo autoimmunity models Nature High 31546246
2024 The late endosomal BORC complex together with the small GTPase Arl8b controls intracellular TLR7 levels by regulating receptor turnover; this requires a direct interaction between TLR7-associated trafficking factor UNC93B1 and Arl8b. An UNC93B1 mutation causing reduced BORC interaction leads to endosomal TLR7 accumulation and childhood-onset lupus. Protein interaction studies (UNC93B1–Arl8b), patient-derived UNC93B1 mutant analysis, endosomal TLR7 level quantification, functional signaling assays Science immunology High 38207015
2020 TASL (encoded by CXorf21) interacts with endolysosomal transporter SLC15A4 and contains a pLxIS motif that mediates recruitment and activation of IRF5; loss of TASL specifically impairs the IRF pathway downstream of TLR7, TLR8, and TLR9 without affecting NF-κB or MAPK signaling, establishing TASL as a TLR7/8/9-to-IRF5 adaptor analogous to STING/MAVS/TRIF for IRF3. Protein interaction studies, TASL knockout in primary and transformed human immune cells, extensive mutagenesis of TASL pLxIS motif, signaling pathway dissection Nature High 32433612
2024 UNC93B1 variants E92G and R336L cause selective TLR7 hyperactivation with constitutive type I IFN signaling; E92G causes UNC93B1 protein instability and reduced interaction with TLR7, demonstrating that UNC93B1 regulates TLR7 subtype-specific ligand recognition mechanisms. Patient-derived cells, mouse macrophages carrying UNC93B1 variants, TLR7/8/9 agonist stimulation assays, protein interaction studies Science immunology High 38207055
2015 TLR7 is present on the cell surface of immune cells (dendritic cells, macrophages, B cells) in addition to endolysosomes; an anti-TLR7 antibody is internalized with TLR7 into endolysosomes and inhibits TLR7 responses and in vivo cytokine production, demonstrating functional cell-surface TLR7. Anti-TLR7 antibody internalization assay, subcellular fractionation/immunofluorescence, in vivo cytokine production, Unc93b1 D34A/D34A autoimmune mouse model treatment Nature communications High 25648980
2021 SHP2 promotes trafficking of TLR7 from the Golgi to the endosome in macrophages by dephosphorylating TLR7 at Tyr1024, which boosts TLR7 ubiquitination and NF-κB-mediated skin inflammation; TLR7 Tyr1024 point-mutant knock-in mice showed attenuated psoriasis-like phenotype. SHP2 allosteric inhibitor, TLR7 point-mutant knock-in mice, subcellular fractionation of TLR7, phosphorylation and ubiquitination assays, conditional SHP2 knockout mice EMBO molecular medicine High 34936223
2009 LL37 antimicrobial peptide binds self-RNA released by dying cells, protects it from extracellular degradation, and transports it into endosomal compartments where it activates TLR7 in plasmacytoid DCs to trigger IFN-α secretion. Co-culture and delivery assays, TLR7 reporter assays, IFN-α ELISA in pDCs, LL37-self-RNA complex characterization Journal of experimental medicine High 19703986
2015 TREML4 is an essential positive regulator of TLR7 signaling; TREML4-deficient macrophages are hyporesponsive to TLR7 agonists due to impaired STAT1 phosphorylation by p38 MAPK and decreased recruitment of adaptor MyD88 to TLR7. Genome-scale shRNA screen, Treml4-/- mice, TLR7 agonist stimulation assays, p38/STAT1 phosphorylation, MyD88 co-immunoprecipitation with TLR7 Nature immunology High 25848864
2010 TLR9 suppresses TLR7-dependent RNA-associated autoantibody production in lupus-prone mice; TLR7-driven disease depends on MyD88; TLR7 and TLR9 act in parallel pathways on different autoantibody subsets with TLR9 also cross-regulating TLR7-dependent responses. Tlr7-/-, Tlr9-/-, double Tlr7/9-/-, and Myd88-/- MRL/lpr mice; autoantibody profiling; disease severity scoring Journal of immunology High 20089701
2007 2'-O-methyl (2'OMe)-modified RNA acts as a potent antagonist of TLR7; it inhibits both RNA-mediated cytokine induction and the small-molecule TLR7 agonist loxoribine without requiring direct incorporation into the immunostimulatory RNA, acting in trans. Human PBMC and murine Flt3L DC cytokine assays, in vivo mouse treatment with loxoribine, 2'OMe antagonist competition assays Molecular therapy Medium 17579574
2013 Inosine incorporation into immunostimulatory ssRNA potentiates TLR7 activation; A-to-I RNA editing of viral ssRNA directly enhances mouse Tlr7 sensing, and inosine-mediated increase in ssRNA self-secondary structure enhances TLR7 (not TLR8)-dependent IFN-α production. TLR7 antagonist, Tlr7-deficient cells, human PBMCs with inosine-modified ssRNAs, influenza ssRNA editing analysis Journal of virology Medium 24227841
2008 TLR7 and CD40 cooperate in B cells to synergistically produce IL-6 through enhanced JNK activity and increased AP-1 (cJun/cFos) activation; dual TLR7+CD40 stimulation markedly enhanced JNK activity and expanded AP-1 dimer species compared to single stimulation. Primary mouse and human B cell stimulation, kinase activity assays (JNK), AP-1 transcription factor analysis, IL-6 cytokine ELISA European journal of immunology Medium 18228247
2019 TLR7 signaling in monocytes specifically increases expression of transcription factor FOSL1, which reduces IL-27 and TNFα production; TLR7 (but not TLR8) activation also stimulates Ca2+ flux in monocytes that prevents type I IFN responses, distinguishing TLR7 and TLR8 as activating distinct signaling cascades. siRNA knockdown of TLR7/TLR8, RNA virus infection of human monocytes, Ca2+ flux assays, cytokine profiling, FOSL1 gain/loss of function Science signaling Medium 31662487
2015 B cell autophagy is required for TLR7-dependent autoimmunity; B cell-specific deletion of Atg5 (autophagy gene) in TLR7-transgenic mice abolished antinuclear antibodies and inflammation, establishing that autophagy delivers RNA ligands to endosomal TLR7 in B cells. Cd19-Cre Atg5f/f × Tlr7 transgenic mice, ANA quantification, inflammatory cytokine measurement, survival analysis Autophagy High 26120731
2019 Chronic TLR7 signaling drives differentiation of inflammatory hemophagocytes (iHPCs) from Ly6Chi monocytes via IRF5; iHPCs are responsible for anemia and thrombocytopenia in TLR7-overexpressing mice. TLR7 signaling specifies monocyte fate through endosomal TLR/MyD88 signaling. TLR7-overexpressing mice, cell lineage tracing, IRF5-deficient mice, endosomal TLR/MyD88 genetic ablation, experimental malaria model Science High 30630901
2022 Purine nucleoside phosphorylase (PNP) regulates TLR7 signaling in B lymphocytes and macrophages by controlling intracellular levels of (deoxy)guanosine nucleoside ligands for TLR7; PNP inactivation leads to accumulation of guanosine ligands, promoting germinal center formation and accelerating autoimmunity. PNP inhibitor/genetic inactivation, TLR7-dependent cytokine assays, mouse autoimmunity model, germinal center formation assays Journal of clinical investigation Medium 35653193
2021 RNase T2-dependent RNA degradation in endosomes/lysosomes positively regulates TLR7 responses in macrophages (and negatively regulates TLR3 responses); RNase T2 mutants (H122A, C188R) that impair RNA degradation also impair TLR7 responses, showing a direct mechanistic link between endosomal RNA processing and TLR7 activation. RNase T2-deficient macrophages, catalytic mutant rescue experiments, in vitro RNA degradation assays, endosomal colocalization studies International immunology Medium 34161582
2018 TLR7 escapes X chromosome inactivation in B lymphocytes, monocytes, and plasmacytoid DCs from women and Klinefelter syndrome males; biallelic B cells show higher TLR7 protein expression and greater than twofold increase in TLR7-driven IgG class switching and CD27+ plasma cell proliferation compared to monoallelic cells. Single-cell allelic expression analysis (SNP-based), TLR7 protein quantification by flow cytometry, B cell functional assays (class switching, plasma cell differentiation) Science immunology High 29374079
2016 Structure-guided mutagenesis of human TLR7 identified specific ectodomain residues governing GS-9620 (TLR7 agonist) binding; TLR7 exists in a ligand-independent oligomeric state, and GS-9620 activation is associated with compound-induced conformational changes. Downstream, GS-9620 activates NF-κB and Akt pathways as immediate responses in pDCs. Structure-guided mutational analysis, subcellular distribution assays, NF-κB/Akt pathway activation in primary pDCs, oligomerization assay PLoS One Medium 26784926
2020 TLR7 activates B cell-intrinsic signaling to drive accelerated lupus in TLR9-deficient mice; B cell-specific TLR7 deletion (CD19-Cre) in TLR9-deficient MRL/lpr mice greatly improved disease, while TLR7 deficiency in CD11c+ cells had no impact, revealing a cis regulatory interaction between TLR7 and TLR9 within the B cell compartment. Conditional TLR7 floxed allele deletion (CD19-Cre and CD11c-Cre), bone marrow chimera strategy, MRL/lpr lupus-prone background JCI insight High 37606042
2023 TLR7 in B cells promotes production of galactose-deficient IgA1 (Gd-IgA1) via the TLR7-GALNT2 axis in IgA nephropathy; TLR7 overexpression increases GALNT2 protein levels while TLR7 knockdown reduces them, and GALNT2 overexpression augments Gd-IgA1 production. TLR7 overexpression and knockdown in B cells, GALNT2 protein quantification, Gd-IgA1 ELISA, patient B cell functional assays JCI insight Medium 32699192
2024 Neuronal substance P induces death of TACR1high cancer cells, releasing extracellular ssRNAs that activate TLR7 in neighboring tumor cells to non-canonically activate a prometastatic gene expression program, driving breast cancer metastasis. 3D co-cultures, in vivo mouse mammary tumor models, TLR7-deficient cancer cells, TACR1 antagonist treatment, gene expression profiling Nature High 39112700
2024 TLR7 gain-of-function interface mutations at the dimerization interface (F507S and L528I) cause systemic and neuroinflammatory disease; the mutations are predicted to enhance TLR7 homodimerization, which enhances TLR7 signaling. Human patient variant identification, structural modeling of dimerization interface, functional signaling assays in patient-derived cells Journal of clinical immunology Medium 38324161
2008 TLR7 and TLR8 activation in human CD34-derived DCs induces DC maturation via JNK and NF-κB; TLR7 (but not TLR8) activation additionally engages the Jak/STAT signaling pathway to drive CD40 expression and cytokine production, while p38MAPK plays a positive role downstream of TLR7 but inhibitory role downstream of TLR8. Selective TLR7 (imiquimod) and TLR8 (3M002) agonists, kinase inhibitor panel, primary human CD34-DCs, cytokine ELISA Journal of leukocyte biology Medium 19164127
2023 TLR7 in dendritic cells promotes neutrophil activation and migration in pustular psoriasis via a TLR7-MyD88-DC-CXCL16 axis; TLR7 induces DC secretion of CXCL16, which activates neutrophils expressing its receptor CXCR6, and this was confirmed in Cd11c-Cre Myd88f/f conditional knockout mice. Conditional MyD88 KO (Cd11c-Cre), Mrp8-Cre Cxcr6f/f KO mice, imiquimod psoriasis model, DC-neutrophil co-culture with TLR7 inhibitor/agonist Cell death & disease Medium 37160878
2023 TLR7 signaling in B cells promotes germinal center formation, affinity maturation, IgG2b/2c isotype switching, and BCR repertoire diversity upon VLP immunization in a B cell-intrinsic manner; chimeric mice lacking TLR7 exclusively in B cells failed to show these enhanced IgG responses. TLR7-deficient chimeric mice with B cell-specific TLR7 deletion, VLP immunization, deep BCR repertoire sequencing, germinal center analysis Frontiers in immunology Medium 35126381
2023 TLR7/8 sensing of lysosomal nucleosides drives histiocytosis in SLC29A3-deficient mice; TLR7 increases phagocyte numbers by driving Ly6Chi monocyte proliferation and maturation, requiring downstream FcRγ and DAP10 for monocyte proliferation. Slc29a3-/- × Tlr7-/- mice, monocyte lineage analysis, FcRγ and DAP10-deficient mice, patient-derived monocyte assays Journal of experimental medicine High 37462944
2023 TLR7 promotes smoke-induced emphysema and COPD through mast cell activity; TLR7 deficiency reduces emphysema severity, TLR7 agonist inhalation alone induces emphysema that is prevented by mast cell stabilizer or mast cell protease-6 (Mcpt6) deficiency, establishing a TLR7→mast cell tryptase pathway in lung damage. TLR7-deficient mice, Mcpt6-deficient mice, imiquimod inhalation model, cromolyn mast cell stabilizer, anti-TLR7 monoclonal antibody treatment Nature communications High 37963864
2024 Tlr7 (X-linked) regulates sex-specific type I interferon responses to myelin; Tlr7 deletion dampens sex differences and protects against demyelination in mouse models of aging and Alzheimer's disease-related tau pathology, with XY sex chromosomes heightening IFN response through Tlr7. Single-nuclei transcriptomics, Tlr7-knockout mice, sex chromosome manipulation (Four Core Genotypes approach), demyelination mouse model, TLR7 inhibitor treatment Science High 39607927

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science (New York, N.Y.) 2579 14976261
2009 Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. The Journal of experimental medicine 581 19703986
2018 TLR7 escapes X chromosome inactivation in immune cells. Science immunology 512 29374079
2022 TLR7 gain-of-function genetic variation causes human lupus. Nature 440 35477763
2010 TLR9 regulates TLR7- and MyD88-dependent autoantibody production and disease in a murine model of lupus. Journal of immunology (Baltimore, Md. : 1950) 278 20089701
2007 2'-O-methyl-modified RNAs act as TLR7 antagonists. Molecular therapy : the journal of the American Society of Gene Therapy 273 17579574
2008 TLR7 and TLR8 as targets in cancer therapy. Oncogene 245 18176600
2020 TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9. Nature 178 32433612
2008 The use of TLR7 and TLR8 ligands for the enhancement of cancer immunotherapy. The oncologist 177 18701762
2019 The TLR7/8 agonist R848 remodels tumor and host responses to promote survival in pancreatic cancer. Nature communications 173 31615993
2012 TLR7 and TLR9 in SLE: when sensing self goes wrong. Immunologic research 164 22434514
2021 TLR3 and TLR7 RNA Sensor Activation during SARS-CoV-2 Infection. Microorganisms 152 34576716
2024 Neuronal substance P drives metastasis through an extracellular RNA-TLR7 axis. Nature 148 39112700
2012 Regulation of TLR7/9 signaling in plasmacytoid dendritic cells. Protein & cell 143 23132256
2019 TLR7 and TLR8 activate distinct pathways in monocytes during RNA virus infection. Science signaling 139 31662487
2018 Female predisposition to TLR7-driven autoimmunity: gene dosage and the escape from X chromosome inactivation. Seminars in immunopathology 138 30276444
2021 SARS-CoV-2-associated ssRNAs activate inflammation and immunity via TLR7/8. JCI insight 118 34375313
2019 UNC93B1 recruits syntenin-1 to dampen TLR7 signalling and prevent autoimmunity. Nature 112 31546246
2020 Interferon lambda promotes immune dysregulation and tissue inflammation in TLR7-induced lupus. Proceedings of the National Academy of Sciences of the United States of America 108 32094169
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
2007 TLR7/9 antagonists as therapeutics for immune-mediated inflammatory disorders. Inflammation & allergy drug targets 101 18220957
2015 B cell autophagy mediates TLR7-dependent autoimmunity and inflammation. Autophagy 100 26120731
2015 Guanosine and its modified derivatives are endogenous ligands for TLR7. International immunology 96 26489884
2009 TLR7 and TLR8 agonists trigger different signaling pathways for human dendritic cell maturation. Journal of leukocyte biology 95 19164127
2020 Trial Watch: experimental TLR7/TLR8 agonists for oncological indications. Oncoimmunology 89 32934889
2019 EV71 infection induces neurodegeneration via activating TLR7 signaling and IL-6 production. PLoS pathogens 86 31730654
2019 Chronic TLR7 and TLR9 signaling drives anemia via differentiation of specialized hemophagocytes. Science (New York, N.Y.) 79 30630901
2009 Emerging roles of TLR7 and TLR9 in murine SLE. Journal of autoimmunity 78 19846276
2008 RNA recognition via TLR7 and TLR8. Handbook of experimental pharmacology 73 18071655
2015 Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases. Nature communications 69 25648980
2018 Dual TLR2 and TLR7 agonists as HIV latency-reversing agents. JCI insight 67 30282829
2011 TLR7 and TLR8 gene variations and susceptibility to hepatitis C virus infection. PloS one 67 22022576
2015 Cell-intrinsic expression of TLR9 in autoreactive B cells constrains BCR/TLR7-dependent responses. Journal of immunology (Baltimore, Md. : 1950) 65 25681333
2024 UNC93B1 variants underlie TLR7-dependent autoimmunity. Science immunology 64 38207055
2014 Modes of action of TLR7 agonists in cancer therapy. Immunotherapy 62 25428647
2015 The receptor TREML4 amplifies TLR7-mediated signaling during antiviral responses and autoimmunity. Nature immunology 61 25848864
2018 Endosomal TLR3, TLR7, and TLR8 control neuronal morphology through different transcriptional programs. The Journal of cell biology 59 29777026
2021 Allosteric inhibition of SHP2 uncovers aberrant TLR7 trafficking in aggravating psoriasis. EMBO molecular medicine 58 34936223
2020 Structural analysis reveals TLR7 dynamics underlying antagonism. Nature communications 58 33060576
2024 Disrupted degradative sorting of TLR7 is associated with human lupus. Science immunology 53 38207015
2014 TLR7, IFNγ, and T-bet: their roles in the development of ABCs in female-biased autoimmunity. Cellular immunology 53 25541140
2008 TLR7 and CD40 cooperate in IL-6 production via enhanced JNK and AP-1 activation. European journal of immunology 53 18228247
2020 TLR7 in B cells promotes renal inflammation and Gd-IgA1 synthesis in IgA nephropathy. JCI insight 50 32699192
2023 The XIST lncRNA is a sex-specific reservoir of TLR7 ligands in SLE. JCI insight 48 37733447
2018 RNA-Based Immunostimulatory Liposomal Spherical Nucleic Acids as Potent TLR7/8 Modulators. Small (Weinheim an der Bergstrasse, Germany) 48 30370991
2008 Porcine TLR8 and TLR7 are both activated by a selective TLR7 ligand, imiquimod. Molecular immunology 48 18439678
2021 Brain innate immune response via miRNA-TLR7 sensing in polymicrobial sepsis. Brain, behavior, and immunity 47 34808293
2013 Identification and characterization of TLR7, TLR8a2, TLR8b1 and TLR8b2 genes in Atlantic salmon (Salmo salar). Developmental and comparative immunology 46 23747412
2023 B cell-intrinsic TLR7 expression drives severe lupus in TLR9-deficient mice. JCI insight 43 37606042
2016 Btk inhibition treats TLR7/IFN driven murine lupus. Clinical immunology (Orlando, Fla.) 43 26821304
2020 TLR7 dosage polymorphism shapes interferogenesis and HIV-1 acute viremia in women. JCI insight 42 32554924
2015 TLR7 and TLR9 ligands regulate antigen presentation by macrophages. International immunology 42 26567289
2013 Increased ribonuclease expression reduces inflammation and prolongs survival in TLR7 transgenic mice. Journal of immunology (Baltimore, Md. : 1950) 42 23382559
2015 TLR7- and TLR9-responsive human B cells share phenotypic and genetic characteristics. Journal of immunology (Baltimore, Md. : 1950) 41 25740945
2014 RNA and imidazoquinolines are sensed by distinct TLR7/8 ectodomain sites resulting in functionally disparate signaling events. Journal of immunology (Baltimore, Md. : 1950) 41 24813206
2012 Cofactors required for TLR7- and TLR9-dependent innate immune responses. Cell host & microbe 41 22423970
2024 Lysosomal endonuclease RNase T2 and PLD exonucleases cooperatively generate RNA ligands for TLR7 activation. Immunity 39 38697119
2022 Antigen epitope-TLR7/8a conjugate as self-assembled carrier-free nanovaccine for personalized immunotherapy. Acta biomaterialia 38 35007785
2022 STING and TLR7/8 agonists-based nanovaccines for synergistic antitumor immune activation. Nano research 38 35464625
2018 The TLR7/8/9 Antagonist IMO-8503 Inhibits Cancer-Induced Cachexia. Cancer research 38 30209066
2022 Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-associated autoimmunity. The Journal of clinical investigation 36 35653193
2024 Interface Gain-of-Function Mutations in TLR7 Cause Systemic and Neuro-inflammatory Disease. Journal of clinical immunology 35 38324161
2009 Characterization of equine and other vertebrate TLR3, TLR7, and TLR8 genes. Immunogenetics 34 19568743
2020 TLR7 endogenous ligands remodel glycolytic macrophages and trigger skin-to-joint crosstalk in psoriatic arthritis. European journal of immunology 33 33079387
2018 Differences in TLR7/8 activation between monocytes and macrophages. Biochemical and biophysical research communications 33 29448098
2017 TLR7 Signaling Regulates Th17 Cells and Autoimmunity: Novel Potential for Autoimmune Therapy. Journal of immunology (Baltimore, Md. : 1950) 33 28652396
2016 The link between TLR7 signaling and hepatitis B virus infection. Life sciences 33 27373425
2021 TLR7 Signaling Drives the Development of Sjögren's Syndrome. Frontiers in immunology 32 34108972
2007 The toll of too much TLR7. Immunity 31 18031693
2024 Tlr7 drives sex differences in age- and Alzheimer's disease-related demyelination. Science (New York, N.Y.) 30 39607927
2013 Inosine-mediated modulation of RNA sensing by Toll-like receptor 7 (TLR7) and TLR8. Journal of virology 30 24227841
2024 Four Core Genotypes mice harbour a 3.2MB X-Y translocation that perturbs Tlr7 dosage. Nature communications 29 39394207
2022 TLR7 Signaling Shapes and Maintains Antibody Diversity Upon Virus-Like Particle Immunization. Frontiers in immunology 29 35126381
2020 TLR7/8 in the Pathogenesis of Parkinson's Disease. International journal of molecular sciences 29 33317145
2020 Role of toll-like receptor 7 (TLR7) in voluntary alcohol consumption. Brain, behavior, and immunity 27 32726684
2018 TLR7-Mediated Lupus Nephritis Is Independent of Type I IFN Signaling. Journal of immunology (Baltimore, Md. : 1950) 27 29884703
2023 Recent Advances on Small-Molecule Antagonists Targeting TLR7. Molecules (Basel, Switzerland) 25 36677692
2022 TLR7 Mediates Acute Respiratory Distress Syndrome in Sepsis by Sensing Extracellular miR-146a. American journal of respiratory cell and molecular biology 25 35679261
2019 Deoxyguanosine is a TLR7 agonist. European journal of immunology 24 31608988
2019 pDC Activation by TLR7/8 Ligand CL097 Compared to TLR7 Ligand IMQ or TLR9 Ligand CpG. Journal of immunology research 22 31093508
2023 TLR7-MyD88-DC-CXCL16 axis results neutrophil activation to elicit inflammatory response in pustular psoriasis. Cell death & disease 21 37160878
2011 Dual or triple activation of TLR7, TLR8, and/or TLR9 by single-stranded oligoribonucleotides. Nucleic acid therapeutics 21 22196370
2023 Vaccination of TLR7/8 Agonist-Conjugated Antigen Nanoparticles for Cancer Immunotherapy. Advanced healthcare materials 20 37016572
2023 TLR7/8 stress response drives histiocytosis in SLC29A3 disorders. The Journal of experimental medicine 20 37462944
2023 TLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase. Nature communications 20 37963864
2022 Keratinocyte TLR2 and TLR7 contribute to chronic itch through pruritic cytokines and chemokines in mice. Journal of cellular physiology 20 36436135
2016 Molecular Determinants of GS-9620-Dependent TLR7 Activation. PloS one 19 26784926
2024 Altered X-chromosome inactivation of the TLR7/8 locus and heterogeneity of pDCs in systemic sclerosis. The Journal of experimental medicine 18 39670995
2021 Skewed endosomal RNA responses from TLR7 to TLR3 in RNase T2-deficient macrophages. International immunology 18 34161582
2020 BBIQ, a pure TLR7 agonist, is an effective influenza vaccine adjuvant. Human vaccines & immunotherapeutics 18 32298200
2015 Involvement of TLR7 and TLR8 in conceptus development and establishment of pregnancy in sheep. Reproduction (Cambridge, England) 18 25602033
2022 HIV-1 infection enhances innate function and TLR7 expression in female plasmacytoid dendritic cells. Life science alliance 17 36271499
2020 TLR7 Expression Is Associated with M2 Macrophage Subset in Calcific Aortic Valve Stenosis. Cells 17 32708790
2022 Covalently Conjugated NOD2/TLR7 Agonists Are Potent and Versatile Immune Potentiators. Journal of medicinal chemistry 16 36335509
2018 Plasmacytoid dendritic cell heterogeneity is defined by CXCL10 expression following TLR7 stimulation. Immunology and cell biology 16 29870118
2018 TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands. Antiviral research 16 29964062
2024 Heterocyclic-Modified Imidazoquinoline Derivatives: Selective TLR7 Agonist Regulates Tumor Microenvironment against Melanoma. Journal of medicinal chemistry 15 38363069
2023 UBE2L3 regulates TLR7-induced B cell autoreactivity in Systemic Lupus Erythematosus. Journal of autoimmunity 14 37001433
2023 TLR7 activation at epithelial barriers promotes emergency myelopoiesis and lung antiviral immunity. eLife 14 37566453

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