{"gene":"IL18R1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1996,"finding":"IL-1Rrp (IL18R1) was cloned as a novel IL-1 receptor family member. A chimeric receptor fusing the IL-1Rrp cytoplasmic domain to the extracellular/transmembrane regions of IL-1R responded to IL-1 stimulation by activating NF-κB and inducing IL-8 promoter function in COS cells, demonstrating that the IL18R1 cytoplasmic domain is capable of transducing intracellular signaling via the NF-κB pathway.","method":"PCR cloning, chimeric receptor transfection into COS cells, NF-κB activation assay, IL-8 promoter reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct functional reconstitution via chimeric receptor transfection with NF-κB and reporter assays in a single rigorous study","pmids":["8626725"],"is_preprint":false},{"year":2001,"finding":"Functional IL-18 signaling requires both the IL-18Rα (IL18R1) and IL-18Rβ chains. COS-1 cells lacking IL-18Rβ did not respond to IL-18 despite expressing IL-18Rα; transfection of IL-18Rβ cDNA into COS-1 cells reconstituted IL-18-induced IL-8 production and luciferase reporter activation. Antibody against IL-18Rα blocked IL-18 responsiveness in cells expressing both chains, confirming that both subunits are required for a functional receptor complex.","method":"Transient transfection of COS-1 cells with IL-18Rβ cDNA, luciferase reporter assay, IL-8 ELISA, anti-IL-18Rα neutralizing antibody blocking experiment","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional reconstitution with receptor subunit transfection, reporter assays, and antibody blocking; multiple orthogonal methods","pmids":["11123287"],"is_preprint":false},{"year":2001,"finding":"IL-1H (a novel IL-1 family member) binds the IL-18 receptor (IL18R1) but not the IL-1 receptor, identifying IL-1H as an additional ligand for the IL-18R axis.","method":"Receptor-binding assay in mammalian cells expressing IL-18R","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, binding assay with expressed receptor, no mutagenesis or structural validation","pmids":["11145836"],"is_preprint":false},{"year":2001,"finding":"IL-12 upregulates steady-state mRNA levels of both IL-18Rα (IL18R1) and IL-18Rβ chains in NKO cells and PBMC, and the IFN-γ production induced by IL-18 plus IL-12 synergism correlates with this IL-12-dependent upregulation of both receptor chains.","method":"Northern/RT-PCR for mRNA quantification, IFN-γ ELISA, flow cytometry","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell types and cytokine conditions tested, two orthogonal readouts (mRNA and protein), single lab","pmids":["11123287"],"is_preprint":false},{"year":2002,"finding":"IL-12-driven upregulation of IL-18Rα on CD4+ T cells is independent of IFN-γ when IL-4 is absent. IFN-γ functions indirectly by limiting the negative effects of IL-4 on IL-18Rα expression during Th1 differentiation; neutralization of IL-4 restored IL-12-driven IL-18Rα upregulation in an IFN-γ-independent manner.","method":"In vitro T cell differentiation assays, cytokine neutralization, flow cytometry for IL-18Rα surface expression, IFN-γ knockout mice","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic (IFN-γ KO mice) and pharmacological (neutralizing antibody) epistasis with multiple conditions, replicated observations","pmids":["12055229"],"is_preprint":false},{"year":2002,"finding":"A 3-base deletion splice variant of IL-18Rα (950delCAG) was identified in atopic patients; PBMCs predominantly expressing this truncated transcript showed significantly reduced IFN-γ production in response to IL-18 stimulation, indicating that this alternative splice form encodes a receptor with impaired signaling capacity.","method":"cDNA sequencing of IL-18Rα from patient PBMCs, RT-PCR for transcript quantification, IFN-γ production assay after IL-18 stimulation","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct correlation of splice variant expression with reduced functional response in patient-derived cells, single lab, two methods","pmids":["11941317"],"is_preprint":false},{"year":2003,"finding":"A truncated splice variant of IL-18Rβ, encoding only the first immunoglobulin-like domain (predicted soluble form), was identified in rat brain cortex, striatum, hypothalamus, hippocampus, liver, and in microglia, astrocytes, and neurons. This variant is rapidly upregulated in microglial cells by LPS, suggesting it may act as a soluble regulator of IL-18 signaling analogous to soluble IL-1R accessory protein.","method":"RT-PCR, cloning, EMBL/GenBank submission, cell culture (pure glial and neuronal cultures), LPS stimulation","journal":"Journal of neuroimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel splice variant cloned and confirmed in multiple tissues and cell types; functional implication proposed but splice variant characterization is direct experimental result","pmids":["14644029"],"is_preprint":false},{"year":2003,"finding":"Human dendritic cells (DC) express IL-18R (IL18R1), and IFN-γ upregulates IL-18R expression on monocyte-derived DCs. IL-18 signaling through IL-18R on DCs directly induces filamentous actin polymerization and cell migration in Boyden chamber assays, establishing IL-18/IL-18R as a novel DC chemotactic pathway.","method":"Flow cytometry for IL-18R surface expression, IFN-γ stimulation, F-actin polymerization assay, Boyden chamber migration assay","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (actin polymerization and migration), single lab","pmids":["14662834"],"is_preprint":false},{"year":2008,"finding":"Transcription factor STAT4 promotes IL18r1 locus expression in Th1 cells, while STAT6 and GATA-3 are required for its repression during Th2 differentiation. GATA-3 binds robustly to conserved non-coding sequences in IL18r1 introns, and ectopic GATA-3 expression in Th1 cells directly repressed IL-18Rα mRNA and surface protein levels. Distinct DNase I hypersensitive (DH) site patterns and histone modifications (H3K4 methylation, histone acetylation) are established at the Il18r1 locus in undifferentiated, Th1, and Th2 cells.","method":"Chromatin remodeling analysis (DNase I hypersensitivity), ChIP for GATA-3 and histone marks, RT-PCR, flow cytometry, ectopic GATA-3 overexpression in Th1 cells, Stat6-deficient Th2 cultures","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct ChIP binding data combined with genetic loss-of-function (Stat6 KO) and gain-of-function (ectopic GATA-3) with multiple chromatin and expression readouts","pmids":["18714006"],"is_preprint":false},{"year":2013,"finding":"IL-18 enhances the physical association between IL-18R heterodimer subunits (IL-18Rα/IL18R1 and IL-18Rβ) and NADPH oxidase subunit Nox1 under basal conditions, as shown by co-immunoprecipitation and GST pull-down assays. This IL-18R/Nox1 interaction promotes Nox1-dependent ROS generation, TRAF3IP2 expression, and IKK/NF-κB and JNK/AP-1 activation, driving human coronary artery smooth muscle cell migration.","method":"Co-immunoprecipitation, GST pull-down, ROS measurement, TRAF3IP2 induction assay, IKK/NF-κB and JNK/AP-1 activation assays, SMC migration assay","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reciprocal Co-IP and GST pulldown demonstrating direct physical association, combined with downstream functional readouts; single lab but multiple orthogonal methods","pmids":["23541442"],"is_preprint":false},{"year":2017,"finding":"T cell-intrinsic expression of IL-18R (IL18R1) and DR3 is required for optimal IFN-γ production in response to non-cognate (TCR-independent) stimulation of CD4+ Th1 cells during Salmonella infection in vivo, while IL-15R expression was dispensable. Mice lacking T cell-intrinsic MyD88 (the adapter downstream of IL-18R) exhibited higher bacterial burdens upon infection with Salmonella, Chlamydia, or Brucella.","method":"In vivo Salmonella infection model, T cell-specific receptor expression analysis by flow cytometry, IL-18R/DR3/IL-15R genetic KO comparison, MyD88 conditional KO, IFN-γ measurement","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo epistasis with multiple KO strains and three different intracellular bacterial pathogens; replicated phenotype across models","pmids":["28817719"],"is_preprint":false},{"year":2017,"finding":"T cell-intrinsic IL-18R/MyD88 signaling (not IL-1R) is required for CD4+ T cell proliferation, protection from apoptosis, and expression of activation/memory genes during Trypanosoma cruzi infection. Il18r1-deficient mice show lower Th1 cell levels and high susceptibility to infection, rescued by adoptive transfer of wild-type CD4+ T cells, placing IL18R1 as a critical upstream activator of the MyD88 pathway for cognate Th1 responses.","method":"Mixed bone-marrow chimeras, transcriptome analysis, flow cytometry, Il18r1 KO mice, IL-1R KO comparison, adoptive transfer rescue experiment","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — mixed BM chimeras establish T cell-intrinsic requirement; IL-1R/IL-18R epistasis with transcriptome; rescue by adoptive transfer; multiple orthogonal methods","pmids":["28895840"],"is_preprint":false},{"year":2020,"finding":"IL-18R (IL18R1) signaling is required for γδ T cell proliferation and generation of cytotoxic GzB+ and IFN-γ-producing γδ T cells during Trypanosoma cruzi infection. Il18r1-deficient mice show drastically reduced γδ T cells, increased intracardiac parasitism, and higher mortality; adoptive transfer of WT γδ T cells rescued Il18r1-deficient mice, confirming an intrinsic requirement for IL-18R in γδ T cell effector function.","method":"Il18r1 KO mice, in vivo infection model, flow cytometry, in vitro proliferation and cytotoxicity assays, adoptive transfer","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with in vivo infection, in vitro mechanistic assays, and adoptive transfer rescue; multiple independent methods","pmids":["32450614"],"is_preprint":false},{"year":2021,"finding":"IL-18R signaling is intrinsically required for short-term HSC (ST-HSC) quiescence during severe Ehrlichia infection-induced shock, but not for HSPC cell death. IFN-αβ promoted IL-18 expression during infection, and IL-18 deficiency prevented bone marrow aplasia and protected HSC/HSPCs. IL-18R-deficient mice showed protected ST-HSCs with maintained quiescence phenotype.","method":"Il18r1 KO mice, Ixodes ovatus Ehrlichia infection model, flow cytometry, bone marrow analysis, IFN-αβ neutralization","journal":"Stem cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with intrinsic requirement demonstrated, separation of quiescence vs death phenotypes with multiple KO models","pmids":["34798063"],"is_preprint":false},{"year":2021,"finding":"Downregulation of IL-18R (IL18R1) surface expression is associated with establishment of tissue residency in kidney CD8+ T cells. TGF-β and IFN-α/β drive IL-18R downregulation during kidney Trm differentiation through TGF-β-dependent suppression of transcription factor Tcf-1. IL-18Rlo expression, combined with CD69, exclusively identifies tissue-resident cells in the kidney, while IL-18Rhi cells include both resident and migratory populations.","method":"Global transcriptional analysis, parabiosis experiments, flow cytometry, TGF-β and IFN-α/β perturbation, Tcf-1 knockout analysis","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — parabiosis (gold standard for tissue residency) combined with cytokine perturbation and transcription factor KO; multiple orthogonal approaches","pmids":["33474536"],"is_preprint":false},{"year":2022,"finding":"T cell-intrinsic IL-18R/MyD88 signaling is required for CD4+ cytotoxic T cell (CD4CTL) differentiation during Trypanosoma cruzi infection. Il18ra-deficient and Myd88-deficient mice phenocopy each other with severely reduced CD4CTL numbers and activity. Mixed BM chimera experiments showed that WT but not Myd88-deficient cells transcribe the CD4CTL gene signature. Adoptive transfer of WT CD4+GzB+ T cells to infected Il18ra mice extended their survival.","method":"Il18ra KO mice, Myd88 KO mice, mixed bone-marrow chimeras, single-cell transcriptomics, flow cytometry, adoptive transfer","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — mixed BM chimeras establish cell-intrinsic requirement; phenocopy between Il18ra and Myd88 KO defines pathway; scRNA-seq and adoptive transfer rescue; replicated across multiple methods","pmids":["35670567"],"is_preprint":false},{"year":2022,"finding":"IL18/IL18R1 signaling promotes NF-κB nuclear translocation and activates the HIF-1 signaling pathway, as demonstrated by proteomic analysis. Macrophage-derived IL-18 acts through IL-18R1 to drive M1 macrophage polarization and synthetic phenotype transformation of vascular smooth muscle cells.","method":"Proteomic analysis, scRNA-seq intercellular communication algorithm (scMLnet), pseudo-time analysis, VIPER transcription factor activity analysis","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — primarily computational/bioinformatic; proteomic and transcriptomic correlations without direct experimental validation of IL18R1-specific NF-κB or HIF-1 activation","pmids":["35069552"],"is_preprint":false},{"year":2022,"finding":"IL-18/IL-18R signaling in astrocytes activates NF-κB and contributes to migraine-like nociceptive behavior. Microglia-produced IL-18 (downstream of TLR4 activation) acts on IL-18R expressed in astrocytes. Blocking IL-18 signaling attenuated nociceptive behavior and suppressed astrocyte activation and NF-κB.","method":"Dural inflammatory soup infusion model, IL-18 pathway blockade, immunohistochemistry, behavioral testing, NF-κB activation assay","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological blockade of IL-18/IL-18R with behavioral and cellular readouts; single lab, multiple methods","pmids":["33137409"],"is_preprint":false},{"year":2022,"finding":"IL-18R-NLRP3 signaling in astrocytes mediates anxiety-like behavior after hemorrhagic shock and resuscitation (HSR). IL-18BP administration blocked IL-18R-NLRP3 signaling, reduced astrocytic activation and pyroptosis markers, and alleviated HSR-induced anxiety; NLRP3-specific agonist partially reversed IL-18BP effects, and astrocyte-specific NLRP3 KO mice showed reduced anxiety-like behavior.","method":"Mouse HSR model, IL-18BP administration, NLRP3 agonist (nigericin), astrocyte-specific NLRP3 KO, behavioral tests (open-field, elevated plus maze), caspase-1/GSDMD/IL-18 protein measurement","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (astrocyte NLRP3 KO) and pharmacological epistasis with behavioral and molecular readouts; single lab","pmids":["36269543"],"is_preprint":false},{"year":2022,"finding":"IL-18/IL-18R signaling suppresses the growth of ILC progenitors (ILCPs) and ILCs by inhibiting proliferation and inducing apoptosis in an IL-18Rα-dependent manner, while being dispensable for early ILC development. Il18r1-deficient lymphoid progenitors generate all ILC subsets normally in vitro and in vivo.","method":"Il18r1 KO mice, in vitro ILC differentiation assay, adoptive transfer, single-cell gene expression analysis, proliferation and apoptosis assays","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with in vitro and in vivo reconstitution, scRNA-seq, adoptive transfer; multiple orthogonal methods; clear separation of IL-18R-dependent and independent phenotypes","pmids":["35874724"],"is_preprint":false},{"year":2024,"finding":"IL-18/IL-18R1 signaling between monocytic lineage cells and CD8+ T cells or NK cells is the top predicted intercellular interaction during STING agonist tumor therapy. Blocking IL-18 reduced IFN-γ production by CD8 T cells in lymph nodes and decreased the therapeutic efficacy of STING agonist treatment in CCR2+/+ but not CCR2-/- mice, placing IL-18R1-mediated signaling as a key axis in monocyte-to-T cell communication during anti-tumor immunity.","method":"scRNA-seq, CCR2-deficient mice, IL-18 blocking antibody, IFN-γ ELISA, STING agonist tumor treatment model","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — scRNA-seq cell-cell interaction prediction supported by in vivo antibody blocking and genetic KO experiment; preprint, single lab","pmids":[],"is_preprint":true},{"year":2024,"finding":"IL-18 acts through IL-18R+ NK cells and T cells in the lung to stimulate IFN-γ production; IFN-γ in turn stimulates ROS-mediated bactericidal activity in neutrophils, restricting Legionella longbeachae infection. Ciliated bronchiolar epithelial cells also express IL-18R but do not contribute to IL-18-mediated bacterial clearance.","method":"In vivo mouse infection model, cell ablation experiments, IFN-γ measurement, ROS assay, IL-18 and IL-18R characterization","journal":"Mucosal immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo cell ablation and functional readouts; single lab; IL-18R pathway placed within a defined IFN-γ/ROS bactericidal cascade","pmids":["38750967"],"is_preprint":false}],"current_model":"IL18R1 (IL-18Rα/CD218a/IL-1Rrp) is the ligand-binding subunit of the heterodimeric IL-18 receptor complex: it binds IL-18 extracellularly and, together with the accessory IL-18Rβ chain (which is required for signal transduction), activates intracellular MyD88/NF-κB and JNK/AP-1 pathways; the receptor physically associates with NADPH oxidase Nox1 to generate ROS; its expression is transcriptionally regulated by STAT4 (induction in Th1 cells) and by GATA-3/STAT6 (repression in Th2 cells), as well as by cytokines including IL-12, IFN-γ, IL-4, TGF-β, and IFN-α/β in a context-dependent manner; T cell-intrinsic IL-18R/MyD88 signaling is essential for Th1 and CD4CTL differentiation, γδ T cell effector function, and non-cognate Th1 activation against intracellular pathogens, while in hematopoietic stem cells it mediates infection-induced quiescence, and its downregulation marks tissue-resident kidney CD8+ T cells."},"narrative":{"mechanistic_narrative":"IL18R1 (IL-18Rα/IL-1Rrp) is the ligand-binding subunit of the IL-18 receptor and functions as a signal-transducing member of the IL-1 receptor family that couples IL-18 sensing to NF-κB activation: a chimeric receptor bearing the IL18R1 cytoplasmic domain activates NF-κB and IL-8 promoter activity, establishing its intrinsic signaling capacity [PMID:8626725]. Functional IL-18 responses require IL18R1 together with the accessory IL-18Rβ chain, as cells expressing IL-18Rα alone are unresponsive until IL-18Rβ is reconstituted [PMID:11123287]. Beyond canonical IL-18, IL18R1 also binds the IL-1 family ligand IL-1H [PMID:11145836]. Ligand engagement drives signaling through the MyD88 adapter, and the receptor additionally associates physically with NADPH oxidase Nox1 to promote ROS generation, TRAF3IP2 induction, and IKK/NF-κB and JNK/AP-1 activation [PMID:23541442]. Receptor abundance is tightly transcriptionally controlled: STAT4 promotes the Il18r1 locus in Th1 cells while STAT6 and GATA-3 repress it during Th2 differentiation, with GATA-3 binding conserved intronic elements and establishing distinct chromatin states [PMID:18714006], and IL-12 upregulates both receptor chains in concert with IFN-γ/IL-4 cross-regulation [PMID:11123287, PMID:12055229]. Functionally, T cell-intrinsic IL18R1/MyD88 signaling is essential for Th1 IFN-γ production, CD4 cytotoxic T cell differentiation, and γδ T cell effector function during intracellular pathogen infection [PMID:28817719, PMID:28895840, PMID:35670567, PMID:32450614], and the axis mediates broader immune outputs including infection-induced hematopoietic stem cell quiescence [PMID:34798063], restraint of innate lymphoid cell expansion [PMID:35874724], and tissue-residency programming of kidney CD8+ T cells through TGF-β/IFN-driven downregulation [PMID:33474536].","teleology":[{"year":1996,"claim":"Established that the orphan IL-1 receptor family member IL-1Rrp possesses an intracellular signaling-competent cytoplasmic domain, defining it as a functional receptor rather than a binding decoy.","evidence":"Chimeric IL-1R/IL-1Rrp receptor transfected into COS cells with NF-κB and IL-8 promoter reporter assays","pmids":["8626725"],"confidence":"High","gaps":["Did not identify the natural ligand","Used a chimeric rather than native receptor","Accessory subunit requirement unaddressed"]},{"year":2001,"claim":"Resolved that a functional IL-18 receptor requires two subunits, identifying IL18R1 as the ligand-binding chain dependent on the IL-18Rβ accessory chain for signal transduction.","evidence":"IL-18Rβ cDNA reconstitution in COS-1 cells, luciferase/IL-8 readouts, anti-IL-18Rα neutralizing antibody; parallel IL-12 mRNA upregulation studies","pmids":["11123287"],"confidence":"High","gaps":["Stoichiometry and structure of the heterodimer not defined","Direct adapter recruitment (MyD88) not shown here"]},{"year":2001,"claim":"Expanded the ligand repertoire of the receptor by showing IL-1H binds IL18R1 but not IL-1R, indicating ligand selectivity within the IL-1 family.","evidence":"Receptor-binding assay in cells expressing IL-18R","pmids":["11145836"],"confidence":"Medium","gaps":["No mutagenesis or structural mapping of the binding interface","Functional consequence of IL-1H binding not established","Single-lab binding assay"]},{"year":2002,"claim":"Defined the cytokine logic controlling receptor surface levels, showing IL-12 drives IL18R1 upregulation primarily by relieving IL-4-mediated repression rather than requiring IFN-γ directly.","evidence":"In vitro Th differentiation, IL-4 neutralization, IFN-γ knockout mice, flow cytometry; alternative splice variant 950delCAG correlated with reduced IL-18 responsiveness in atopic patients","pmids":["12055229","11941317"],"confidence":"High","gaps":["Transcription factors mediating the IL-12 effect not yet identified","Splice variant functional impact correlative, not mechanistically dissected"]},{"year":2008,"claim":"Established the transcriptional and chromatin basis of lineage-specific receptor expression, with STAT4 activating and GATA-3/STAT6 repressing the Il18r1 locus across Th1/Th2 fates.","evidence":"DNase I hypersensitivity mapping, GATA-3 and histone ChIP, Stat6 KO, ectopic GATA-3 overexpression, RT-PCR/flow cytometry","pmids":["18714006"],"confidence":"High","gaps":["STAT4 direct binding less defined than GATA-3 repression","Connection between chromatin state and downstream signaling output not addressed"]},{"year":2013,"claim":"Identified a non-canonical receptor partner, showing IL18R1 physically associates with Nox1 to couple IL-18 sensing to ROS-dependent NF-κB/AP-1 activation.","evidence":"Co-immunoprecipitation, GST pull-down, ROS measurement, TRAF3IP2/IKK/JNK assays, smooth muscle cell migration","pmids":["23541442"],"confidence":"High","gaps":["Direct vs indirect nature of the IL18R1-Nox1 interaction not fully resolved","Generality of the Nox1 axis beyond vascular smooth muscle unknown"]},{"year":2017,"claim":"Demonstrated that T cell-intrinsic IL18R1/MyD88 signaling is a critical upstream driver of Th1 IFN-γ responses against intracellular bacteria and protozoa, both cognate and non-cognate.","evidence":"Salmonella in vivo model with IL-18R/DR3/IL-15R KO comparison and T cell MyD88 conditional KO; T. cruzi model with mixed BM chimeras, Il18r1 KO, IL-1R comparison, transcriptomics, adoptive transfer rescue","pmids":["28817719","28895840"],"confidence":"High","gaps":["Molecular events linking IL18R1 to MyD88 in T cells not biochemically dissected","Distinction from IL-1R signaling defined functionally, not structurally"]},{"year":2021,"claim":"Extended IL18R1 function beyond effector differentiation, showing it intrinsically enforces hematopoietic stem cell quiescence during infection and marks the loss of tissue residency in kidney CD8+ T cells.","evidence":"Il18r1 KO mice in Ehrlichia shock model with IFN-αβ neutralization; parabiosis, TGF-β/IFN perturbation and Tcf-1 KO in kidney Trm analysis","pmids":["34798063","33474536"],"confidence":"High","gaps":["Mechanism coupling IL18R1 signaling to quiescence vs death unresolved","How receptor downregulation is mechanistically enforced during residency not fully defined"]},{"year":2022,"claim":"Showed IL18R1/MyD88 signaling drives CD4 cytotoxic T cell and γδ T cell effector programs while restraining ILC expansion, broadening its role across lymphocyte lineages.","evidence":"Il18ra and Myd88 KO phenocopy with mixed BM chimeras, scRNA-seq and adoptive transfer (CD4CTL, γδ T cells); Il18r1 KO ILC differentiation assays with proliferation/apoptosis readouts","pmids":["35670567","32450614","35874724"],"confidence":"High","gaps":["Lineage-specific downstream effectors not fully mapped","Why IL18R1 promotes effector cells but suppresses ILCs mechanistically unexplained"]},{"year":2022,"claim":"Implicated IL18R1 signaling in non-lymphoid contexts including astrocyte NF-κB/NLRP3 activation in CNS pain and anxiety models.","evidence":"Migraine soup and hemorrhagic shock models with IL-18 blockade/IL-18BP, astrocyte NLRP3 KO, behavioral and molecular readouts","pmids":["33137409","36269543"],"confidence":"Medium","gaps":["Direct IL18R1 engagement on astrocytes vs paracrine effects not isolated","Single-lab models for each phenotype"]},{"year":2024,"claim":"Positioned IL18R1 as a key node in monocyte-to-lymphocyte communication driving anti-tumor and anti-bacterial IFN-γ responses.","evidence":"scRNA-seq intercellular prediction, CCR2 KO mice, IL-18 blockade in STING agonist tumor model (preprint); in vivo Legionella infection with cell ablation and ROS/IFN-γ readouts","pmids":["38750967"],"confidence":"Medium","gaps":["Tumor study is a preprint with predicted interactions","Receptor-level (vs ligand-level) intervention not performed"]},{"year":null,"claim":"The structural basis of IL-18/IL18R1/IL-18Rβ assembly and the proximal biochemical steps linking the receptor to MyD88 recruitment in T cells remain undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of the ternary receptor complex in the corpus","Proximal adapter recruitment events not biochemically resolved","IL-1H functional signaling consequences unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,9]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,7,9]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,11,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,14]}],"complexes":["IL-18 receptor complex (IL-18Rα/IL-18Rβ)"],"partners":["IL18RAP","NOX1","MYD88","IL18","IL37"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13478","full_name":"Interleukin-18 receptor 1","aliases":["CD218 antigen-like family member A","CDw218a","IL1 receptor-related protein","IL-1Rrp","IL1R-rp","Interleukin-18 receptor alpha","IL-18R-alpha","IL-18Ralpha"],"length_aa":541,"mass_kda":62.3,"function":"Within the IL18 receptor complex, responsible for the binding of the pro-inflammatory cytokine IL18, but not IL1A nor IL1B (PubMed:14528293, PubMed:25261253, PubMed:25500532, PubMed:37993714, PubMed:8626725). Involved in IL18-mediated IFNG synthesis from T-helper 1 (Th1) cells (PubMed:10653850). Contributes to IL18-induced cytokine production, either independently of SLC12A3, or as a complex with SLC12A3 (By similarity)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q13478/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL18R1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL18R1","total_profiled":1310},"omim":[{"mim_id":"612006","title":"CELIAC DISEASE, SUSCEPTIBILITY TO, 8; CELIAC8","url":"https://www.omim.org/entry/612006"},{"mim_id":"609888","title":"LEPROSY, SUSCEPTIBILITY TO, 1; LPRS1","url":"https://www.omim.org/entry/609888"},{"mim_id":"604512","title":"INTERLEUKIN 1 RECEPTOR-LIKE 2; IL1RL2","url":"https://www.omim.org/entry/604512"},{"mim_id":"604509","title":"INTERLEUKIN 18 RECEPTOR ACCESSORY PROTEIN; IL18RAP","url":"https://www.omim.org/entry/604509"},{"mim_id":"604494","title":"INTERLEUKIN 18 RECEPTOR 1; IL18R1","url":"https://www.omim.org/entry/604494"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lung","ntpm":11.3}],"url":"https://www.proteinatlas.org/search/IL18R1"},"hgnc":{"alias_symbol":["IL-18R","IL1RRP","IL-1Rrp","CD218a"],"prev_symbol":[]},"alphafold":{"accession":"Q13478","domains":[{"cath_id":"2.60.40.10","chopping":"28-44_53-113","consensus_level":"high","plddt":87.1901,"start":28,"end":113},{"cath_id":"2.60.40.10","chopping":"123-208","consensus_level":"high","plddt":92.2538,"start":123,"end":208},{"cath_id":"2.60.40.10","chopping":"217-316","consensus_level":"high","plddt":91.1247,"start":217,"end":316},{"cath_id":"3.40.50.10140","chopping":"363-520","consensus_level":"high","plddt":71.1397,"start":363,"end":520}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13478","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13478-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13478-F1-predicted_aligned_error_v6.png","plddt_mean":79.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL18R1","jax_strain_url":"https://www.jax.org/strain/search?query=IL18R1"},"sequence":{"accession":"Q13478","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13478.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13478/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13478"}},"corpus_meta":[{"pmid":"8626725","id":"PMC_8626725","title":"IL-1Rrp is a novel receptor-like molecule similar to the type I interleukin-1 receptor and its homologues T1/ST2 and IL-1R AcP.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8626725","citation_count":197,"is_preprint":false},{"pmid":"11145836","id":"PMC_11145836","title":"IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp.","date":"2001","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/11145836","citation_count":169,"is_preprint":false},{"pmid":"12055229","id":"PMC_12055229","title":"Role of IFN-gamma in Th1 differentiation: IFN-gamma regulates IL-18R alpha expression by preventing the negative effects of IL-4 and by inducing/maintaining IL-12 receptor beta 2 expression.","date":"2002","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/12055229","citation_count":103,"is_preprint":false},{"pmid":"10191101","id":"PMC_10191101","title":"Interleukin-1 receptor cluster: gene organization of IL1R2, IL1R1, IL1RL2 (IL-1Rrp2), IL1RL1 (T1/ST2), and IL18R1 (IL-1Rrp) on human chromosome 2q.","date":"1999","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10191101","citation_count":88,"is_preprint":false},{"pmid":"12684057","id":"PMC_12684057","title":"TNF-alpha and H2O2 induce IL-18 and IL-18R beta expression in cardiomyocytes via NF-kappa B activation.","date":"2003","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12684057","citation_count":79,"is_preprint":false},{"pmid":"22968128","id":"PMC_22968128","title":"Role of P2X7 receptor-mediated IL-18/IL-18R signaling in morphine tolerance: multiple glial-neuronal dialogues in the rat spinal cord.","date":"2012","source":"The journal of pain","url":"https://pubmed.ncbi.nlm.nih.gov/22968128","citation_count":77,"is_preprint":false},{"pmid":"14662834","id":"PMC_14662834","title":"Human dendritic cells express the IL-18R and are chemoattracted to IL-18.","date":"2003","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/14662834","citation_count":77,"is_preprint":false},{"pmid":"11123287","id":"PMC_11123287","title":"Functional reconstitution and regulation of IL-18 activity by the IL-18R beta chain.","date":"2001","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11123287","citation_count":73,"is_preprint":false},{"pmid":"28508444","id":"PMC_28508444","title":"Increased adipose tissue expression of IL-18R and its ligand IL-18 associates with inflammation and insulin resistance in obesity.","date":"2017","source":"Immunity, inflammation and disease","url":"https://pubmed.ncbi.nlm.nih.gov/28508444","citation_count":49,"is_preprint":false},{"pmid":"10865972","id":"PMC_10865972","title":"Expression and responsiveness of human interleukin-18 receptor (IL-18R) on hematopoietic cell lines.","date":"2000","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/10865972","citation_count":48,"is_preprint":false},{"pmid":"19225717","id":"PMC_19225717","title":"Expression of interleukin-18, IL-18BP, and IL-18R in serum, synovial fluid, and synovial tissue in patients with rheumatoid arthritis.","date":"2009","source":"Clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19225717","citation_count":43,"is_preprint":false},{"pmid":"25108227","id":"PMC_25108227","title":"Pressure overload induces IL-18 and IL-18R expression, but markedly suppresses IL-18BP expression in a rabbit model. IL-18 potentiates TNF-α-induced cardiomyocyte death.","date":"2014","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/25108227","citation_count":42,"is_preprint":false},{"pmid":"22039448","id":"PMC_22039448","title":"Contributions of the MyD88-dependent receptors IL-18R, IL-1R, and TLR9 to host defenses following pulmonary challenge with Cryptococcus neoformans.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22039448","citation_count":38,"is_preprint":false},{"pmid":"14644029","id":"PMC_14644029","title":"Identification of a truncated IL-18R beta mRNA: a putative regulator of IL-18 expressed in rat brain.","date":"2003","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/14644029","citation_count":36,"is_preprint":false},{"pmid":"33137409","id":"PMC_33137409","title":"Microglia-Astrocyte Cross Talk through IL-18/IL-18R Signaling Modulates Migraine-like Behavior in Experimental Models of Migraine.","date":"2020","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/33137409","citation_count":35,"is_preprint":false},{"pmid":"21742843","id":"PMC_21742843","title":"Common SNPs/haplotypes in IL18R1 and IL18 genes are associated with variations in humoral immunity to smallpox vaccination in Caucasians and African Americans.","date":"2011","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21742843","citation_count":30,"is_preprint":false},{"pmid":"28817719","id":"PMC_28817719","title":"T cell expression of IL-18R and DR3 is essential for non-cognate stimulation of Th1 cells and optimal clearance of intracellular bacteria.","date":"2017","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/28817719","citation_count":27,"is_preprint":false},{"pmid":"35069552","id":"PMC_35069552","title":"Cardiovascular Risk After SARS-CoV-2 Infection Is Mediated by IL18/IL18R1/HIF-1 Signaling Pathway Axis.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35069552","citation_count":25,"is_preprint":false},{"pmid":"18714006","id":"PMC_18714006","title":"Transcription factor-dependent chromatin remodeling of Il18r1 during Th1 and Th2 differentiation.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18714006","citation_count":23,"is_preprint":false},{"pmid":"18547159","id":"PMC_18547159","title":"Constitutive expression of IL-18 and IL-18R in differentiated IEC-6 cells: effect of TNF-alpha and IFN-gamma treatment.","date":"2008","source":"Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/18547159","citation_count":23,"is_preprint":false},{"pmid":"26688048","id":"PMC_26688048","title":"T cell responses are elicited against Respiratory Syncytial Virus in the absence of signalling through TLRs, RLRs and IL-1R/IL-18R.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26688048","citation_count":23,"is_preprint":false},{"pmid":"22550553","id":"PMC_22550553","title":"An Association Study of Interleukin 18 Receptor Genes (IL18R1 and IL18RAP) in Lumbar Disc Degeneration.","date":"2012","source":"The open orthopaedics journal","url":"https://pubmed.ncbi.nlm.nih.gov/22550553","citation_count":22,"is_preprint":false},{"pmid":"31914650","id":"PMC_31914650","title":"IL-18R-dependent and independent pathways account for IL-18-enhanced antitumor ability of CAR-T cells.","date":"2019","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/31914650","citation_count":21,"is_preprint":false},{"pmid":"35670567","id":"PMC_35670567","title":"Cytotoxic CD4+ T cells driven by T-cell intrinsic IL-18R/MyD88 signaling predominantly infiltrate Trypanosoma cruzi-infected hearts.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/35670567","citation_count":21,"is_preprint":false},{"pmid":"28895840","id":"PMC_28895840","title":"Crucial role for T cell-intrinsic IL-18R-MyD88 signaling in cognate immune response to intracellular parasite infection.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28895840","citation_count":21,"is_preprint":false},{"pmid":"28922563","id":"PMC_28922563","title":"Role of IL-18 in atopic asthma is determined by balance of IL-18/IL-18BP/IL-18R.","date":"2017","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28922563","citation_count":19,"is_preprint":false},{"pmid":"20580925","id":"PMC_20580925","title":"Behavioral and genetic investigations of low exploratory behavior in Il18r1(-/-) mice: we can't always blame it on the targeted gene.","date":"2010","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/20580925","citation_count":19,"is_preprint":false},{"pmid":"35201443","id":"PMC_35201443","title":"New immunological potential markers for triple negative breast cancer: IL18R1, CD53, TRIM, Jaw1, LTB, PTPRCAP.","date":"2021","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35201443","citation_count":19,"is_preprint":false},{"pmid":"39572158","id":"PMC_39572158","title":"IL-18R supported CAR T cells targeting oncofetal tenascin C for the immunotherapy of pediatric sarcoma and brain tumors.","date":"2024","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39572158","citation_count":18,"is_preprint":false},{"pmid":"23541442","id":"PMC_23541442","title":"Interleukin-18 enhances IL-18R/Nox1 binding, and mediates TRAF3IP2-dependent smooth muscle cell migration. Inhibition by simvastatin.","date":"2013","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/23541442","citation_count":17,"is_preprint":false},{"pmid":"16971411","id":"PMC_16971411","title":"IL18 and IL18R1 polymorphisms, lung CT and fibrosis: A longitudinal study in coal miners.","date":"2006","source":"The European respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/16971411","citation_count":16,"is_preprint":false},{"pmid":"23901078","id":"PMC_23901078","title":"Genetic variation in IL18R1 and IL18 genes and Inteferon γ ELISPOT response to smallpox vaccination: an unexpected relationship.","date":"2013","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/23901078","citation_count":16,"is_preprint":false},{"pmid":"11941317","id":"PMC_11941317","title":"Predominant expression of 950delCAG of IL-18R alpha chain cDNA is associated with reduced IFN-gamma production and high serum IgE levels in atopic Japanese children.","date":"2002","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11941317","citation_count":16,"is_preprint":false},{"pmid":"26566691","id":"PMC_26566691","title":"Polymorphisms of ST2-IL18R1-IL18RAP gene cluster: a new risk for autoimmune thyroid diseases.","date":"2015","source":"International journal of immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/26566691","citation_count":14,"is_preprint":false},{"pmid":"33474536","id":"PMC_33474536","title":"The downregulation of IL-18R defines bona fide kidney-resident CD8+ T cells.","date":"2021","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/33474536","citation_count":14,"is_preprint":false},{"pmid":"19473509","id":"PMC_19473509","title":"Lack of association between polymorphisms of the IL18R1 and IL18RAP genes and cardiovascular risk: the MORGAM Project.","date":"2009","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19473509","citation_count":13,"is_preprint":false},{"pmid":"34798063","id":"PMC_34798063","title":"IL-18R-mediated HSC quiescence and MLKL-dependent cell death limit hematopoiesis during infection-induced shock.","date":"2021","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34798063","citation_count":12,"is_preprint":false},{"pmid":"24955184","id":"PMC_24955184","title":"Association between gene polymorphisms in TIM1, TSLP, IL18R1 and childhood asthma in Turkish population.","date":"2014","source":"International journal of clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24955184","citation_count":12,"is_preprint":false},{"pmid":"14994387","id":"PMC_14994387","title":"Expression of interleukin 12 receptor (IL-12R) and IL-18R on CD4+ T cells from patients with rheumatoid arthritis.","date":"2004","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/14994387","citation_count":12,"is_preprint":false},{"pmid":"36269543","id":"PMC_36269543","title":"IL-18BP Alleviates Anxiety-Like Behavior Induced by Traumatic Stress via Inhibition of the IL-18R-NLRP3 Signaling Pathway in a Mouse Model of Hemorrhagic Shock and Resuscitation.","date":"2022","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/36269543","citation_count":10,"is_preprint":false},{"pmid":"35874724","id":"PMC_35874724","title":"IL-18/IL-18R Signaling Is Dispensable for ILC Development But Constrains the Growth of ILCP/ILCs.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35874724","citation_count":8,"is_preprint":false},{"pmid":"33103874","id":"PMC_33103874","title":"Increased expression of serum IL-18 and IL-18R in newly diagnosed type 2 diabetes mellitus.","date":"2020","source":"Minerva endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/33103874","citation_count":7,"is_preprint":false},{"pmid":"32450614","id":"PMC_32450614","title":"IL-18R signaling is required for γδ T cell response and confers resistance to Trypanosoma cruzi infection.","date":"2020","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/32450614","citation_count":7,"is_preprint":false},{"pmid":"38750967","id":"PMC_38750967","title":"Opposing roles of resident and infiltrating immune cells in the defense against Legionella longbeachae via IL-18R/IFN-γ/ROS axis in mice.","date":"2024","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38750967","citation_count":3,"is_preprint":false},{"pmid":"40430016","id":"PMC_40430016","title":"The Potential Contribution of the IL-37/IL-18/IL-18BP/IL-18R Axis in the Pathogenesis of Sjögren's Syndrome.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40430016","citation_count":2,"is_preprint":false},{"pmid":"39847405","id":"PMC_39847405","title":"Identification of genetic variants of the IL18R1 gene in association with COPD susceptibility.","date":"2025","source":"Annals of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39847405","citation_count":2,"is_preprint":false},{"pmid":"41562052","id":"PMC_41562052","title":"Serologic IL-18 increase with B-cell IL-18R loss characterizes selective IgA deficiency.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41562052","citation_count":1,"is_preprint":false},{"pmid":"29285382","id":"PMC_29285382","title":"IL18 rs360719 A>G, IL18R1 rs13015714 G>T, IL18RAP rs917997 C>T and IL28B rs8099917 T>G polymorphisms and risk of gastric cardiac adenocarcinoma.","date":"2017","source":"Molecular and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29285382","citation_count":1,"is_preprint":false},{"pmid":"41154589","id":"PMC_41154589","title":"Predicted IL-18/IL-18R Binding Improvement Through Protein Interface Modification with Computer-Aided Design.","date":"2025","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41154589","citation_count":0,"is_preprint":false},{"pmid":"40777291","id":"PMC_40777291","title":"Activation of IL-17+ ILC subsets in IL-18R-deficient mice during fungal allergen exposure.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40777291","citation_count":0,"is_preprint":false},{"pmid":"41111914","id":"PMC_41111914","title":"Identification of IL18/IL18R1 signaling as a predictive biomarker of SGLT2 inhibitor efficacy in type 2 diabetes.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/41111914","citation_count":0,"is_preprint":false},{"pmid":"40226003","id":"PMC_40226003","title":"Serum IL-18R1 and its effect on immune cell infiltration in asthma.","date":"2025","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/40226003","citation_count":0,"is_preprint":false},{"pmid":"40784338","id":"PMC_40784338","title":"Characteristics of Asthmatic Patients with IL18R1 Differential Expression in Induced Sputum.","date":"2025","source":"International archives of allergy and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40784338","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.04.25339477","title":"Plasma proteome signatures are predictive of mortality in sickle cell disease","date":"2025-11-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.04.25339477","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.08.25331132","title":"Brain network and blood transcriptomic correlations underpin psychopathological phenotypes: A Preliminary Study","date":"2025-07-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.08.25331132","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.05.652166","title":"Identification of a novel transcriptome signature for predicting the response to anti-TNF-α treatment in rheumatoid arthritis patients","date":"2025-05-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.05.652166","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.05.25332853","title":"Distinct modulatory effects of high-fiber and fermented-food diets on gut microbiota, immune function, transit time, and sleep quality in a citizen science randomized controlled trial","date":"2025-08-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.05.25332853","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.08.627385","title":"STING agonists drive recruitment and intrinsic type I interferon responses in monocytic lineage cells for optimal anti-tumor immunity","date":"2024-12-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.08.627385","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.20.25340712","title":"Comprehensive genomic atlas of plasma proteome in the Japanese population: the Nagahama study","date":"2025-11-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.20.25340712","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":33216,"output_tokens":6330,"usd":0.097299,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15333,"output_tokens":4087,"usd":0.08942,"stage2_stop_reason":"end_turn"},"total_usd":0.186719,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"IL-1Rrp (IL18R1) was cloned as a novel IL-1 receptor family member. A chimeric receptor fusing the IL-1Rrp cytoplasmic domain to the extracellular/transmembrane regions of IL-1R responded to IL-1 stimulation by activating NF-κB and inducing IL-8 promoter function in COS cells, demonstrating that the IL18R1 cytoplasmic domain is capable of transducing intracellular signaling via the NF-κB pathway.\",\n      \"method\": \"PCR cloning, chimeric receptor transfection into COS cells, NF-κB activation assay, IL-8 promoter reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct functional reconstitution via chimeric receptor transfection with NF-κB and reporter assays in a single rigorous study\",\n      \"pmids\": [\"8626725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Functional IL-18 signaling requires both the IL-18Rα (IL18R1) and IL-18Rβ chains. COS-1 cells lacking IL-18Rβ did not respond to IL-18 despite expressing IL-18Rα; transfection of IL-18Rβ cDNA into COS-1 cells reconstituted IL-18-induced IL-8 production and luciferase reporter activation. Antibody against IL-18Rα blocked IL-18 responsiveness in cells expressing both chains, confirming that both subunits are required for a functional receptor complex.\",\n      \"method\": \"Transient transfection of COS-1 cells with IL-18Rβ cDNA, luciferase reporter assay, IL-8 ELISA, anti-IL-18Rα neutralizing antibody blocking experiment\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional reconstitution with receptor subunit transfection, reporter assays, and antibody blocking; multiple orthogonal methods\",\n      \"pmids\": [\"11123287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-1H (a novel IL-1 family member) binds the IL-18 receptor (IL18R1) but not the IL-1 receptor, identifying IL-1H as an additional ligand for the IL-18R axis.\",\n      \"method\": \"Receptor-binding assay in mammalian cells expressing IL-18R\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, binding assay with expressed receptor, no mutagenesis or structural validation\",\n      \"pmids\": [\"11145836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-12 upregulates steady-state mRNA levels of both IL-18Rα (IL18R1) and IL-18Rβ chains in NKO cells and PBMC, and the IFN-γ production induced by IL-18 plus IL-12 synergism correlates with this IL-12-dependent upregulation of both receptor chains.\",\n      \"method\": \"Northern/RT-PCR for mRNA quantification, IFN-γ ELISA, flow cytometry\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell types and cytokine conditions tested, two orthogonal readouts (mRNA and protein), single lab\",\n      \"pmids\": [\"11123287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IL-12-driven upregulation of IL-18Rα on CD4+ T cells is independent of IFN-γ when IL-4 is absent. IFN-γ functions indirectly by limiting the negative effects of IL-4 on IL-18Rα expression during Th1 differentiation; neutralization of IL-4 restored IL-12-driven IL-18Rα upregulation in an IFN-γ-independent manner.\",\n      \"method\": \"In vitro T cell differentiation assays, cytokine neutralization, flow cytometry for IL-18Rα surface expression, IFN-γ knockout mice\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic (IFN-γ KO mice) and pharmacological (neutralizing antibody) epistasis with multiple conditions, replicated observations\",\n      \"pmids\": [\"12055229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A 3-base deletion splice variant of IL-18Rα (950delCAG) was identified in atopic patients; PBMCs predominantly expressing this truncated transcript showed significantly reduced IFN-γ production in response to IL-18 stimulation, indicating that this alternative splice form encodes a receptor with impaired signaling capacity.\",\n      \"method\": \"cDNA sequencing of IL-18Rα from patient PBMCs, RT-PCR for transcript quantification, IFN-γ production assay after IL-18 stimulation\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct correlation of splice variant expression with reduced functional response in patient-derived cells, single lab, two methods\",\n      \"pmids\": [\"11941317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A truncated splice variant of IL-18Rβ, encoding only the first immunoglobulin-like domain (predicted soluble form), was identified in rat brain cortex, striatum, hypothalamus, hippocampus, liver, and in microglia, astrocytes, and neurons. This variant is rapidly upregulated in microglial cells by LPS, suggesting it may act as a soluble regulator of IL-18 signaling analogous to soluble IL-1R accessory protein.\",\n      \"method\": \"RT-PCR, cloning, EMBL/GenBank submission, cell culture (pure glial and neuronal cultures), LPS stimulation\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel splice variant cloned and confirmed in multiple tissues and cell types; functional implication proposed but splice variant characterization is direct experimental result\",\n      \"pmids\": [\"14644029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human dendritic cells (DC) express IL-18R (IL18R1), and IFN-γ upregulates IL-18R expression on monocyte-derived DCs. IL-18 signaling through IL-18R on DCs directly induces filamentous actin polymerization and cell migration in Boyden chamber assays, establishing IL-18/IL-18R as a novel DC chemotactic pathway.\",\n      \"method\": \"Flow cytometry for IL-18R surface expression, IFN-γ stimulation, F-actin polymerization assay, Boyden chamber migration assay\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (actin polymerization and migration), single lab\",\n      \"pmids\": [\"14662834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Transcription factor STAT4 promotes IL18r1 locus expression in Th1 cells, while STAT6 and GATA-3 are required for its repression during Th2 differentiation. GATA-3 binds robustly to conserved non-coding sequences in IL18r1 introns, and ectopic GATA-3 expression in Th1 cells directly repressed IL-18Rα mRNA and surface protein levels. Distinct DNase I hypersensitive (DH) site patterns and histone modifications (H3K4 methylation, histone acetylation) are established at the Il18r1 locus in undifferentiated, Th1, and Th2 cells.\",\n      \"method\": \"Chromatin remodeling analysis (DNase I hypersensitivity), ChIP for GATA-3 and histone marks, RT-PCR, flow cytometry, ectopic GATA-3 overexpression in Th1 cells, Stat6-deficient Th2 cultures\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct ChIP binding data combined with genetic loss-of-function (Stat6 KO) and gain-of-function (ectopic GATA-3) with multiple chromatin and expression readouts\",\n      \"pmids\": [\"18714006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-18 enhances the physical association between IL-18R heterodimer subunits (IL-18Rα/IL18R1 and IL-18Rβ) and NADPH oxidase subunit Nox1 under basal conditions, as shown by co-immunoprecipitation and GST pull-down assays. This IL-18R/Nox1 interaction promotes Nox1-dependent ROS generation, TRAF3IP2 expression, and IKK/NF-κB and JNK/AP-1 activation, driving human coronary artery smooth muscle cell migration.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, ROS measurement, TRAF3IP2 induction assay, IKK/NF-κB and JNK/AP-1 activation assays, SMC migration assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reciprocal Co-IP and GST pulldown demonstrating direct physical association, combined with downstream functional readouts; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23541442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"T cell-intrinsic expression of IL-18R (IL18R1) and DR3 is required for optimal IFN-γ production in response to non-cognate (TCR-independent) stimulation of CD4+ Th1 cells during Salmonella infection in vivo, while IL-15R expression was dispensable. Mice lacking T cell-intrinsic MyD88 (the adapter downstream of IL-18R) exhibited higher bacterial burdens upon infection with Salmonella, Chlamydia, or Brucella.\",\n      \"method\": \"In vivo Salmonella infection model, T cell-specific receptor expression analysis by flow cytometry, IL-18R/DR3/IL-15R genetic KO comparison, MyD88 conditional KO, IFN-γ measurement\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo epistasis with multiple KO strains and three different intracellular bacterial pathogens; replicated phenotype across models\",\n      \"pmids\": [\"28817719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"T cell-intrinsic IL-18R/MyD88 signaling (not IL-1R) is required for CD4+ T cell proliferation, protection from apoptosis, and expression of activation/memory genes during Trypanosoma cruzi infection. Il18r1-deficient mice show lower Th1 cell levels and high susceptibility to infection, rescued by adoptive transfer of wild-type CD4+ T cells, placing IL18R1 as a critical upstream activator of the MyD88 pathway for cognate Th1 responses.\",\n      \"method\": \"Mixed bone-marrow chimeras, transcriptome analysis, flow cytometry, Il18r1 KO mice, IL-1R KO comparison, adoptive transfer rescue experiment\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mixed BM chimeras establish T cell-intrinsic requirement; IL-1R/IL-18R epistasis with transcriptome; rescue by adoptive transfer; multiple orthogonal methods\",\n      \"pmids\": [\"28895840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-18R (IL18R1) signaling is required for γδ T cell proliferation and generation of cytotoxic GzB+ and IFN-γ-producing γδ T cells during Trypanosoma cruzi infection. Il18r1-deficient mice show drastically reduced γδ T cells, increased intracardiac parasitism, and higher mortality; adoptive transfer of WT γδ T cells rescued Il18r1-deficient mice, confirming an intrinsic requirement for IL-18R in γδ T cell effector function.\",\n      \"method\": \"Il18r1 KO mice, in vivo infection model, flow cytometry, in vitro proliferation and cytotoxicity assays, adoptive transfer\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with in vivo infection, in vitro mechanistic assays, and adoptive transfer rescue; multiple independent methods\",\n      \"pmids\": [\"32450614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-18R signaling is intrinsically required for short-term HSC (ST-HSC) quiescence during severe Ehrlichia infection-induced shock, but not for HSPC cell death. IFN-αβ promoted IL-18 expression during infection, and IL-18 deficiency prevented bone marrow aplasia and protected HSC/HSPCs. IL-18R-deficient mice showed protected ST-HSCs with maintained quiescence phenotype.\",\n      \"method\": \"Il18r1 KO mice, Ixodes ovatus Ehrlichia infection model, flow cytometry, bone marrow analysis, IFN-αβ neutralization\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with intrinsic requirement demonstrated, separation of quiescence vs death phenotypes with multiple KO models\",\n      \"pmids\": [\"34798063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Downregulation of IL-18R (IL18R1) surface expression is associated with establishment of tissue residency in kidney CD8+ T cells. TGF-β and IFN-α/β drive IL-18R downregulation during kidney Trm differentiation through TGF-β-dependent suppression of transcription factor Tcf-1. IL-18Rlo expression, combined with CD69, exclusively identifies tissue-resident cells in the kidney, while IL-18Rhi cells include both resident and migratory populations.\",\n      \"method\": \"Global transcriptional analysis, parabiosis experiments, flow cytometry, TGF-β and IFN-α/β perturbation, Tcf-1 knockout analysis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — parabiosis (gold standard for tissue residency) combined with cytokine perturbation and transcription factor KO; multiple orthogonal approaches\",\n      \"pmids\": [\"33474536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"T cell-intrinsic IL-18R/MyD88 signaling is required for CD4+ cytotoxic T cell (CD4CTL) differentiation during Trypanosoma cruzi infection. Il18ra-deficient and Myd88-deficient mice phenocopy each other with severely reduced CD4CTL numbers and activity. Mixed BM chimera experiments showed that WT but not Myd88-deficient cells transcribe the CD4CTL gene signature. Adoptive transfer of WT CD4+GzB+ T cells to infected Il18ra mice extended their survival.\",\n      \"method\": \"Il18ra KO mice, Myd88 KO mice, mixed bone-marrow chimeras, single-cell transcriptomics, flow cytometry, adoptive transfer\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mixed BM chimeras establish cell-intrinsic requirement; phenocopy between Il18ra and Myd88 KO defines pathway; scRNA-seq and adoptive transfer rescue; replicated across multiple methods\",\n      \"pmids\": [\"35670567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL18/IL18R1 signaling promotes NF-κB nuclear translocation and activates the HIF-1 signaling pathway, as demonstrated by proteomic analysis. Macrophage-derived IL-18 acts through IL-18R1 to drive M1 macrophage polarization and synthetic phenotype transformation of vascular smooth muscle cells.\",\n      \"method\": \"Proteomic analysis, scRNA-seq intercellular communication algorithm (scMLnet), pseudo-time analysis, VIPER transcription factor activity analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — primarily computational/bioinformatic; proteomic and transcriptomic correlations without direct experimental validation of IL18R1-specific NF-κB or HIF-1 activation\",\n      \"pmids\": [\"35069552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-18/IL-18R signaling in astrocytes activates NF-κB and contributes to migraine-like nociceptive behavior. Microglia-produced IL-18 (downstream of TLR4 activation) acts on IL-18R expressed in astrocytes. Blocking IL-18 signaling attenuated nociceptive behavior and suppressed astrocyte activation and NF-κB.\",\n      \"method\": \"Dural inflammatory soup infusion model, IL-18 pathway blockade, immunohistochemistry, behavioral testing, NF-κB activation assay\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological blockade of IL-18/IL-18R with behavioral and cellular readouts; single lab, multiple methods\",\n      \"pmids\": [\"33137409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-18R-NLRP3 signaling in astrocytes mediates anxiety-like behavior after hemorrhagic shock and resuscitation (HSR). IL-18BP administration blocked IL-18R-NLRP3 signaling, reduced astrocytic activation and pyroptosis markers, and alleviated HSR-induced anxiety; NLRP3-specific agonist partially reversed IL-18BP effects, and astrocyte-specific NLRP3 KO mice showed reduced anxiety-like behavior.\",\n      \"method\": \"Mouse HSR model, IL-18BP administration, NLRP3 agonist (nigericin), astrocyte-specific NLRP3 KO, behavioral tests (open-field, elevated plus maze), caspase-1/GSDMD/IL-18 protein measurement\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (astrocyte NLRP3 KO) and pharmacological epistasis with behavioral and molecular readouts; single lab\",\n      \"pmids\": [\"36269543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-18/IL-18R signaling suppresses the growth of ILC progenitors (ILCPs) and ILCs by inhibiting proliferation and inducing apoptosis in an IL-18Rα-dependent manner, while being dispensable for early ILC development. Il18r1-deficient lymphoid progenitors generate all ILC subsets normally in vitro and in vivo.\",\n      \"method\": \"Il18r1 KO mice, in vitro ILC differentiation assay, adoptive transfer, single-cell gene expression analysis, proliferation and apoptosis assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with in vitro and in vivo reconstitution, scRNA-seq, adoptive transfer; multiple orthogonal methods; clear separation of IL-18R-dependent and independent phenotypes\",\n      \"pmids\": [\"35874724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-18/IL-18R1 signaling between monocytic lineage cells and CD8+ T cells or NK cells is the top predicted intercellular interaction during STING agonist tumor therapy. Blocking IL-18 reduced IFN-γ production by CD8 T cells in lymph nodes and decreased the therapeutic efficacy of STING agonist treatment in CCR2+/+ but not CCR2-/- mice, placing IL-18R1-mediated signaling as a key axis in monocyte-to-T cell communication during anti-tumor immunity.\",\n      \"method\": \"scRNA-seq, CCR2-deficient mice, IL-18 blocking antibody, IFN-γ ELISA, STING agonist tumor treatment model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — scRNA-seq cell-cell interaction prediction supported by in vivo antibody blocking and genetic KO experiment; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-18 acts through IL-18R+ NK cells and T cells in the lung to stimulate IFN-γ production; IFN-γ in turn stimulates ROS-mediated bactericidal activity in neutrophils, restricting Legionella longbeachae infection. Ciliated bronchiolar epithelial cells also express IL-18R but do not contribute to IL-18-mediated bacterial clearance.\",\n      \"method\": \"In vivo mouse infection model, cell ablation experiments, IFN-γ measurement, ROS assay, IL-18 and IL-18R characterization\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo cell ablation and functional readouts; single lab; IL-18R pathway placed within a defined IFN-γ/ROS bactericidal cascade\",\n      \"pmids\": [\"38750967\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL18R1 (IL-18Rα/CD218a/IL-1Rrp) is the ligand-binding subunit of the heterodimeric IL-18 receptor complex: it binds IL-18 extracellularly and, together with the accessory IL-18Rβ chain (which is required for signal transduction), activates intracellular MyD88/NF-κB and JNK/AP-1 pathways; the receptor physically associates with NADPH oxidase Nox1 to generate ROS; its expression is transcriptionally regulated by STAT4 (induction in Th1 cells) and by GATA-3/STAT6 (repression in Th2 cells), as well as by cytokines including IL-12, IFN-γ, IL-4, TGF-β, and IFN-α/β in a context-dependent manner; T cell-intrinsic IL-18R/MyD88 signaling is essential for Th1 and CD4CTL differentiation, γδ T cell effector function, and non-cognate Th1 activation against intracellular pathogens, while in hematopoietic stem cells it mediates infection-induced quiescence, and its downregulation marks tissue-resident kidney CD8+ T cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL18R1 (IL-18Rα/IL-1Rrp) is the ligand-binding subunit of the IL-18 receptor and functions as a signal-transducing member of the IL-1 receptor family that couples IL-18 sensing to NF-κB activation: a chimeric receptor bearing the IL18R1 cytoplasmic domain activates NF-κB and IL-8 promoter activity, establishing its intrinsic signaling capacity [#0]. Functional IL-18 responses require IL18R1 together with the accessory IL-18Rβ chain, as cells expressing IL-18Rα alone are unresponsive until IL-18Rβ is reconstituted [#1]. Beyond canonical IL-18, IL18R1 also binds the IL-1 family ligand IL-1H [#2]. Ligand engagement drives signaling through the MyD88 adapter, and the receptor additionally associates physically with NADPH oxidase Nox1 to promote ROS generation, TRAF3IP2 induction, and IKK/NF-κB and JNK/AP-1 activation [#9]. Receptor abundance is tightly transcriptionally controlled: STAT4 promotes the Il18r1 locus in Th1 cells while STAT6 and GATA-3 repress it during Th2 differentiation, with GATA-3 binding conserved intronic elements and establishing distinct chromatin states [#8], and IL-12 upregulates both receptor chains in concert with IFN-γ/IL-4 cross-regulation [#3, #4]. Functionally, T cell-intrinsic IL18R1/MyD88 signaling is essential for Th1 IFN-γ production, CD4 cytotoxic T cell differentiation, and γδ T cell effector function during intracellular pathogen infection [#10, #11, #15, #12], and the axis mediates broader immune outputs including infection-induced hematopoietic stem cell quiescence [#13], restraint of innate lymphoid cell expansion [#19], and tissue-residency programming of kidney CD8+ T cells through TGF-β/IFN-driven downregulation [#14].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that the orphan IL-1 receptor family member IL-1Rrp possesses an intracellular signaling-competent cytoplasmic domain, defining it as a functional receptor rather than a binding decoy.\",\n      \"evidence\": \"Chimeric IL-1R/IL-1Rrp receptor transfected into COS cells with NF-κB and IL-8 promoter reporter assays\",\n      \"pmids\": [\"8626725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the natural ligand\", \"Used a chimeric rather than native receptor\", \"Accessory subunit requirement unaddressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Resolved that a functional IL-18 receptor requires two subunits, identifying IL18R1 as the ligand-binding chain dependent on the IL-18Rβ accessory chain for signal transduction.\",\n      \"evidence\": \"IL-18Rβ cDNA reconstitution in COS-1 cells, luciferase/IL-8 readouts, anti-IL-18Rα neutralizing antibody; parallel IL-12 mRNA upregulation studies\",\n      \"pmids\": [\"11123287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structure of the heterodimer not defined\", \"Direct adapter recruitment (MyD88) not shown here\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Expanded the ligand repertoire of the receptor by showing IL-1H binds IL18R1 but not IL-1R, indicating ligand selectivity within the IL-1 family.\",\n      \"evidence\": \"Receptor-binding assay in cells expressing IL-18R\",\n      \"pmids\": [\"11145836\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis or structural mapping of the binding interface\", \"Functional consequence of IL-1H binding not established\", \"Single-lab binding assay\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the cytokine logic controlling receptor surface levels, showing IL-12 drives IL18R1 upregulation primarily by relieving IL-4-mediated repression rather than requiring IFN-γ directly.\",\n      \"evidence\": \"In vitro Th differentiation, IL-4 neutralization, IFN-γ knockout mice, flow cytometry; alternative splice variant 950delCAG correlated with reduced IL-18 responsiveness in atopic patients\",\n      \"pmids\": [\"12055229\", \"11941317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factors mediating the IL-12 effect not yet identified\", \"Splice variant functional impact correlative, not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established the transcriptional and chromatin basis of lineage-specific receptor expression, with STAT4 activating and GATA-3/STAT6 repressing the Il18r1 locus across Th1/Th2 fates.\",\n      \"evidence\": \"DNase I hypersensitivity mapping, GATA-3 and histone ChIP, Stat6 KO, ectopic GATA-3 overexpression, RT-PCR/flow cytometry\",\n      \"pmids\": [\"18714006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"STAT4 direct binding less defined than GATA-3 repression\", \"Connection between chromatin state and downstream signaling output not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified a non-canonical receptor partner, showing IL18R1 physically associates with Nox1 to couple IL-18 sensing to ROS-dependent NF-κB/AP-1 activation.\",\n      \"evidence\": \"Co-immunoprecipitation, GST pull-down, ROS measurement, TRAF3IP2/IKK/JNK assays, smooth muscle cell migration\",\n      \"pmids\": [\"23541442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect nature of the IL18R1-Nox1 interaction not fully resolved\", \"Generality of the Nox1 axis beyond vascular smooth muscle unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated that T cell-intrinsic IL18R1/MyD88 signaling is a critical upstream driver of Th1 IFN-γ responses against intracellular bacteria and protozoa, both cognate and non-cognate.\",\n      \"evidence\": \"Salmonella in vivo model with IL-18R/DR3/IL-15R KO comparison and T cell MyD88 conditional KO; T. cruzi model with mixed BM chimeras, Il18r1 KO, IL-1R comparison, transcriptomics, adoptive transfer rescue\",\n      \"pmids\": [\"28817719\", \"28895840\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular events linking IL18R1 to MyD88 in T cells not biochemically dissected\", \"Distinction from IL-1R signaling defined functionally, not structurally\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended IL18R1 function beyond effector differentiation, showing it intrinsically enforces hematopoietic stem cell quiescence during infection and marks the loss of tissue residency in kidney CD8+ T cells.\",\n      \"evidence\": \"Il18r1 KO mice in Ehrlichia shock model with IFN-αβ neutralization; parabiosis, TGF-β/IFN perturbation and Tcf-1 KO in kidney Trm analysis\",\n      \"pmids\": [\"34798063\", \"33474536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling IL18R1 signaling to quiescence vs death unresolved\", \"How receptor downregulation is mechanistically enforced during residency not fully defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed IL18R1/MyD88 signaling drives CD4 cytotoxic T cell and γδ T cell effector programs while restraining ILC expansion, broadening its role across lymphocyte lineages.\",\n      \"evidence\": \"Il18ra and Myd88 KO phenocopy with mixed BM chimeras, scRNA-seq and adoptive transfer (CD4CTL, γδ T cells); Il18r1 KO ILC differentiation assays with proliferation/apoptosis readouts\",\n      \"pmids\": [\"35670567\", \"32450614\", \"35874724\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lineage-specific downstream effectors not fully mapped\", \"Why IL18R1 promotes effector cells but suppresses ILCs mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated IL18R1 signaling in non-lymphoid contexts including astrocyte NF-κB/NLRP3 activation in CNS pain and anxiety models.\",\n      \"evidence\": \"Migraine soup and hemorrhagic shock models with IL-18 blockade/IL-18BP, astrocyte NLRP3 KO, behavioral and molecular readouts\",\n      \"pmids\": [\"33137409\", \"36269543\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct IL18R1 engagement on astrocytes vs paracrine effects not isolated\", \"Single-lab models for each phenotype\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Positioned IL18R1 as a key node in monocyte-to-lymphocyte communication driving anti-tumor and anti-bacterial IFN-γ responses.\",\n      \"evidence\": \"scRNA-seq intercellular prediction, CCR2 KO mice, IL-18 blockade in STING agonist tumor model (preprint); in vivo Legionella infection with cell ablation and ROS/IFN-γ readouts\",\n      \"pmids\": [\"38750967\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tumor study is a preprint with predicted interactions\", \"Receptor-level (vs ligand-level) intervention not performed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of IL-18/IL18R1/IL-18Rβ assembly and the proximal biochemical steps linking the receptor to MyD88 recruitment in T cells remain undefined.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the ternary receptor complex in the corpus\", \"Proximal adapter recruitment events not biochemically resolved\", \"IL-1H functional signaling consequences unestablished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 7, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 11, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 14]}\n    ],\n    \"complexes\": [\"IL-18 receptor complex (IL-18Rα/IL-18Rβ)\"],\n    \"partners\": [\"IL18RAP\", \"NOX1\", \"MYD88\", \"IL18\", \"IL37\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}