Affinage

CXCR1

C-X-C chemokine receptor type 1 · UniProt P25024

Length
350 aa
Mass
39.8 kDa
Annotated
2026-06-09
100 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CXCR1 is a seven-transmembrane, G protein-coupled chemokine receptor that binds IL-8/CXCL8 and selectively the mouse ligand GCP-2/CXCL6 to drive neutrophil and leukocyte effector functions in innate host defense (PMID:17197447). Ligand recognition follows a membrane-constrained two-site logic: the isolated N-terminal domain binds IL-8 with micromolar affinity and adopts a structured, membrane-interacting conformation only in a micelle/bilayer environment, a conformational constraint that governs ligand selectivity at site I (PMID:15133028), while the assembled receptor undergoes rapid rotational diffusion in the bilayer with mobile termini and dynamically restricted transmembrane helices (PMID:21323370). Beyond canonical Gi coupling, CXCR1 activates a Gi-independent Rho/Rho-kinase cascade that builds actin stress fibers (PMID:11350788) and uniquely engages PKCε to mediate receptor exocytosis and cross-desensitization of CCR5 (PMID:15905535). Agonist binding triggers GRK2/β-arrestin/dynamin-dependent clathrin-mediated internalization controlled by a C-terminal cluster of phosphorylation sites, with subsequent recycling to the surface (PMID:10347185, PMID:10623425); CXCL8 monomer is the more potent driver of phosphorylation, β-arrestin recruitment and internalization than the dimer (PMID:19667085). CXCR1 constitutively forms homo- and heterodimers with CXCR2 assembled during biosynthesis (PMID:15946947), and distinct second-extracellular-loop determinants set its slower internalization kinetics relative to CXCR2 (PMID:17204468). Functionally, CXCR1 is required cell-intrinsically for neutrophil degranulation and microbial killing in candidiasis and anti-Pseudomonas pulmonary defense, independent of trafficking, with a human CXCR1-T276 variant impairing this effector arm (PMID:26791948, PMID:26950764). Its expression is transcriptionally induced under hypoxia by HIF-1 and NF-κB binding to the CXCR1 promoter (PMID:17533374), and CXCR1 signaling extends to dendritic cell cytokine production via a CXCL5/HIF-1α feedback loop (PMID:37709757) and to breast cancer stem cell survival, where blockade triggers FAS/FASL apoptosis through the FAK/AKT/FOXO3A pathway (PMID:20051626).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1993 Medium

    Establishing the genomic identity and locus of the high-affinity IL-8 receptor was the foundational step that defined CXCR1 as a discrete gene distinct from its low-affinity counterpart.

    Evidence PCR cloning, Southern blotting and in situ hybridization mapping to chromosome 2q33-q36

    PMID:8486366

    Open questions at the time
    • Does not address receptor function or ligand specificity
    • No protein-level characterization
  2. 1999 High

    The internalization machinery and the C-terminal determinant controlling it were defined, distinguishing CXCR1 desensitization from CXCR2.

    Evidence Dominant-negative GRK2/β-arrestin1/dynamin constructs with CXCR1-GFP and C-terminal deletion mutants in HEK293/RBL-2H3 cells

    PMID:10347185 PMID:10623425

    Open questions at the time
    • Specific phosphorylated residues among the six sites not individually mapped
    • Kinetics in primary neutrophils not assessed
  3. 2001 High

    CXCR1 was shown to drive a Gi-independent Rho/Rho-kinase signaling arm, separating its cytoskeletal output from CXCR2's Gi/Rac-mediated response.

    Evidence Dominant-negative Rho/Rac, C3 toxin, Y-27632, pertussis toxin and receptor-blocking antibodies in microvascular endothelial cells

    PMID:11350788

    Open questions at the time
    • Upstream link between receptor and Rho activation not defined
    • Endothelial-specific vs leukocyte signaling not compared
  4. 2004 High

    NMR demonstrated that membrane environment constrains the N-domain conformation, providing the structural basis for site-I ligand selectivity.

    Evidence Solution and detergent-micelle NMR of the isolated CXCR1 N-domain with IL-8 and MGSA binding measurements

    PMID:15133028

    Open questions at the time
    • Isolated peptide, not full-length receptor in native membrane
    • Site-II contribution not addressed here
  5. 2005 High

    CXCR1 was found to constitutively dimerize with itself and CXCR2 during biosynthesis, and to uniquely couple to PKCε for exocytosis and CCR5 cross-desensitization.

    Evidence BRET/FRET/co-IP with ER trapping in HEK293; PKCε inhibitor peptide, PKCε-/- macrophages and CXCR1/CXCR2 chimeras

    PMID:15905535 PMID:15946947

    Open questions at the time
    • Functional consequence of heterodimerization on signaling output not fully resolved
    • PKCε activation mechanism downstream of receptor unknown
  6. 2006 High

    Cloning of mouse CXCR1 established its ligand specificity (GCP-2/CXCL6 and human IL-8) and validated a tractable ortholog for in vivo study.

    Evidence Radioligand binding, GTPγS exchange and chemotaxis of mCXCR1 transfectants against a ligand panel

    PMID:17197447

    Open questions at the time
    • Endogenous mouse ligand in vivo not defined
    • Receptor signaling differences between species not characterized
  7. 2007 High

    The second extracellular loop, and specifically Asp199 in CXCR2, was identified as the structural switch governing the divergent internalization kinetics of the two receptors.

    Evidence CXCR1/CXCR2 domain swaps and D199V/D199N point mutants with comprehensive functional assays in RBL-2H3 cells

    PMID:17204468

    Open questions at the time
    • How 2ECL identity is transmitted to the endocytic machinery is unresolved
    • Physiological relevance of kinetic difference not tested
  8. 2007 High

    Hypoxic transcriptional control of CXCR1 was established by direct HIF-1 and NF-κB binding to its promoter.

    Evidence ChIP, siRNA, HIF-1 dominant-negative and pharmacological inhibitors in PC3 prostate cancer cells

    PMID:17533374

    Open questions at the time
    • Promoter element coordinates not detailed
    • Relevance to neutrophil/immune cell expression not tested
  9. 2009 High

    Ligand oligomeric state was shown to bias CXCR1 responses, with the CXCL8 monomer driving more rapid phosphorylation, β-arrestin translocation and internalization than the dimer.

    Evidence Trapped CXCL8 monomer (L25NMe) and dimer (R26C) across neutrophils and CXCR1/CXCR2 RBL cells with multiple functional readouts; dynamic FRET dimer analysis

    PMID:19667085 PMID:19890050

    Open questions at the time
    • Structural basis for monomer preference at CXCR1 not defined
    • Quantitative dimer/monomer balance in vivo unknown
  10. 2011 High

    Solid-state and solution NMR of full-length CXCR1 in bilayers defined its rotational dynamics and the restricted mobility of transmembrane helices in a native-like environment.

    Evidence Solution NMR in bicelles and solid-state NMR of aligned bilayers with full-length and truncated constructs

    PMID:21323370

    Open questions at the time
    • No high-resolution atomic structure of the receptor
    • Ligand-bound dynamics not captured
  11. 2016 High

    Genetic dissection in mice and a human variant showed CXCR1's host-defense role lies in cell-intrinsic neutrophil degranulation and microbial killing, not trafficking.

    Evidence Cxcr1-/- mouse candidiasis and Pseudomonas airway models, ROS/TLR5 analysis, and CXCR1-T276 patient neutrophil function

    PMID:26791948 PMID:26950764

    Open questions at the time
    • Molecular link from CXCR1 to degranulation/ROS not fully mapped
    • Mechanism of TLR5 modulation unknown
  12. 2016 Medium

    Accessory proteins REEP5/6 were identified as CXCR1-selective partners required for ligand-stimulated endocytosis and downstream signaling.

    Evidence Co-IP, overexpression and siRNA of REEP5/6 with internalization, β-arrestin2 clustering, ERK and actin assays; A549 xenograft

    PMID:27966653

    Open questions at the time
    • Structural basis of CXCR1-REEP interaction unknown
    • Single-lab co-IP without reciprocal in vivo validation
  13. 2016 Medium

    CXCR1 was shown to control hepatocyte exosome biogenesis and cargo packaging, extending its role beyond chemotaxis to vesicle-mediated intercellular signaling.

    Evidence CXCR1-/- and CXCR2-/- hepatocytes with exosome quantification, sphingomyelinase/ceramide assays and proliferation readouts

    PMID:27551720

    Open questions at the time
    • Signaling pathway from receptor to exosome machinery undefined
    • Ligand driving this hepatocyte function unknown
  14. 2010 High

    CXCR1 blockade was shown to selectively kill breast cancer stem cells, defining a non-immune oncogenic function via FAS/FASL and FAK/AKT/FOXO3A signaling.

    Evidence Repertaxin and blocking antibody in breast cancer cell lines, ALDH/flow CSC quantification, pathway analysis and NOD/SCID xenografts

    PMID:20051626

    Open questions at the time
    • Endogenous ligand sustaining CSC survival not identified
    • Direct receptor-to-FAK coupling mechanism unresolved
  15. 2012 Medium

    Pathogen-derived and pharmacological ligands clarified CXCR1's druggable allosteric pocket and its exploitation by viral mimics.

    Evidence DF2156A allosteric inhibitor binding via Lys99 (radioligand/GTPγS/chemotaxis with modeling) and HIV-1 p17 high-affinity binding driving angiogenesis via ERK/Akt

    PMID:21718305 PMID:22904195

    Open questions at the time
    • Allosteric mechanism not validated structurally
    • Physiological consequence of p17 engagement in HIV infection unclear
  16. 2018 Medium

    Posttranslationally modified CXCL8 forms were shown to modulate CXCR1 internalization and signaling magnitude without altering the Gαi/β-arrestin bias.

    Evidence Synthetic CXCL8(6-77) and [Cit5]CXCL8 variants in neutrophil internalization, HTRF Gαi and β-arrestin recruitment assays

    PMID:30486423

    Open questions at the time
    • In vivo abundance and relevance of modified ligands unknown
    • Structural basis of altered potency undefined
  17. 2023 Medium

    DC-specific deletion established a CXCL5/CXCR1/HIF-1α feedback loop controlling IL-6 and IL-12 production and inflammatory disease severity.

    Evidence Global and DC-specific CXCR1 knockout mice in EAE and ARDS models with CXCL5 neutralization and HIF-1α pathway analysis

    PMID:37709757

    Open questions at the time
    • Direct CXCR1-HIF-1α coupling mechanism in DCs not resolved
    • Whether feedback operates in human DCs untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CXCR1's distinct downstream effectors (Rho/Rho-kinase, PKCε, REEP5/6, exosome machinery) are selectively engaged by a single receptor, and what governs ligand-, dimer-, and tissue-specific output, remains unresolved.
  • No high-resolution ligand-bound structure to rationalize biased signaling
  • Mechanistic link from receptor to tissue-specific effector programs (degranulation, exosomes, CSC survival) not unified
  • Endogenous human ligand specificity in each context incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0001618 virus receptor activity 2 GO:0048018 receptor ligand activity 2
Localization
GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-5653656 Vesicle-mediated transport 3
Partners
ARRB1CBLCXCR2DNM1GRK2PRKCEREEP5REEP6
Complex memberships
CXCR1-CXCR2 homo/heterodimer

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 IL-8 activation of CXCR1 on microvascular endothelial cells induces early-phase actin stress fiber formation via a Rho/Rho-kinase signaling cascade (blocked by C3 botulinum toxin and Y-27632, but not pertussis toxin), distinct from CXCR2-mediated later-phase cell retraction via Gi and Rac. Dominant-negative Rho and Rac overexpression, C3 botulinum toxin, pertussis toxin treatment, CXCR1/CXCR2-specific blocking antibodies in microvascular endothelial cells American journal of physiology. Lung cellular and molecular physiology High 11350788
1999 Agonist-induced CXCR1 internalization requires GRK2, beta-arrestins, and dynamin, and proceeds via clathrin-coated vesicles; dominant-negative beta-arrestin 1-V53D and dynamin I-K44A both block CXCR1-GFP internalization. CXCR1-GFP fusion protein expression in HEK293 and RBL-2H3 cells; co-expression of dominant-negative GRK2, beta-arrestin 1-V53D, dynamin I-K44A; co-localization with transferrin in endosomes by fluorescence microscopy The Journal of biological chemistry High 10347185
1999 IL-8-induced internalization of CXCR1 is dependent on a carboxyl-terminal region containing six phosphorylation sites, whereas CXCR2 internalization is primarily regulated by a membrane-proximal C-terminal domain lacking phosphorylation sites; both receptors recycle back to the plasma membrane after ligand removal. HEK293 cell transfectants with CXCR1 and CXCR2 C-terminal deletion/mutation constructs; receptor internalization and recycling assays Cytokine Medium 10623425
2004 The CXCR1 N-terminal domain (N-domain) binds IL-8 with ~1 µM affinity in detergent micelles (mimicking membrane environment) versus ~20 µM in solution, and adopts a structured, membrane-interacting extended conformation in micelles; MGSA/GRO-alpha also binds the N-domain in micelles (~3 µM) but not in solution, indicating that conformational constraint by the membrane environment governs ligand selectivity at site I. Solution NMR and detergent-micelle NMR of the isolated CXCR1 N-domain peptide; binding affinity measurements with IL-8 and MGSA The Journal of biological chemistry High 15133028
2005 CXCR1 and CXCR2 form constitutive homo- and heterodimers with equal apparent affinities, initiated during protein biosynthesis prior to cell-surface delivery; these interactions are unaffected by IL-8 agonist treatment. Co-immunoprecipitation, single-cell FRET imaging, cell-surface time-resolved FRET, bioluminescence resonance energy transfer (BRET) saturation assays, ER-trapping strategy in HEK293 cells The Journal of biological chemistry High 15946947
2005 CXCR1 specifically activates PKCε (but not PKCα, -β1, or -β2) in human mononuclear phagocytes; PKCε mediates CXCR1-dependent receptor exocytosis and cross-desensitization of CCR5 but not phosphoinositide hydrolysis or peak Ca2+ mobilization. PKC isoform plasma membrane association assays, PKCε inhibitor peptide (εV1) expression, PKCε-/- peritoneal macrophages, CXCR1/CXCR2 chimeric receptor (ΔCxcr2) in RBL-2H3 cells Journal of immunology High 15905535
2007 The second extracellular loop (2ECL) of CXCR2, specifically Asp199, is a critical structural determinant that drives CXCR2's rapid internalization kinetics relative to CXCR1; replacing CXCR2 Asp199 with CXCR1's valine (or swapping the entire 2ECL) converts CXCR2 internalization kinetics to match CXCR1. Chimeric and point-mutant receptor constructs (CXCR1/CXCR2 domain swaps and D199V, D199N mutations) stably expressed in RBL-2H3 cells; receptor binding, Ca2+ mobilization, phosphoinositide hydrolysis, phosphorylation, internalization, MAPK activation assays; structural modeling of 2ECL The Journal of biological chemistry High 17204468
2009 CXCL8 monomer (trapped non-associating form) is more potent than dimer for Ca2+ mobilization, phosphoinositide hydrolysis, chemotaxis, and exocytosis; monomer more rapidly induces CXCR1 phosphorylation, desensitization, β-arrestin translocation, and internalization relative to dimer, while CXCR2 responds similarly to both forms; ERK phosphorylation is more sustained via CXCR2 than CXCR1. Trapped CXCL8 monomer (L25NMe) and non-dissociating dimer (R26C) used with human neutrophils and RBL cells stably expressing CXCR1 or CXCR2; Ca2+ mobilization, phosphoinositide hydrolysis, chemotaxis, exocytosis, receptor phosphorylation, β-arrestin translocation, internalization, ERK phosphorylation assays Journal of immunology High 19667085
2009 CXCR1 and CXCR2 form dynamic homo- and heterodimers in human neutrophils; CXCL8 stabilizes homodimers and promotes receptor internalization while altering heterodimeric complexes; receptor expression level and ligand activation regulate the balance between homo- and heterodimer states. FRET techniques in human neutrophils and co-expressing cell lines; receptor expression manipulation and ligand activation experiments Journal of immunology Medium 19890050
2011 CXCR1 undergoes rapid rotational diffusion about the bilayer normal in liquid-crystalline phospholipid bilayers; the N- and C-termini are mobile, while transmembrane helices and interhelical loops show restricted backbone dynamics; only ~13% of expected backbone amide resonances are observed in solution NMR due to limited local mobility of TM regions. Solution NMR (1H/15N HSQC, TROSY) in isotropic bicelles; solid-state NMR of magnetically aligned bilayers and unoriented bilayers with full-length and truncated CXCR1 constructs; 13C and 15N chemical shift powder patterns Biochemistry High 21323370
2012 The dual CXCR1/CXCR2 allosteric inhibitor DF2156A binds CXCR1 through a polar interaction network including a direct ionic bond with Lys99 on CXCR1, acting as a non-competitive allosteric inhibitor that blocks signal transduction leading to chemotaxis without altering natural ligand binding affinity. Radioligand binding assays, [35S]-GTPγS binding, chemotaxis assays with L1.2 transfectants and human leukocytes; mutagenesis/modeling of binding contacts (Lys99 on CXCR1, Asp293 on CXCR2) British journal of pharmacology Medium 21718305
2016 In Candida albicans systemic infection, CXCR1 (Cxcr1) is required for neutrophil degranulation (a cell-intrinsic effector function) and fungal killing in the kidney, but not for neutrophil trafficking from blood into infected tissue; the human CXCR1-T276 mutant allele similarly impairs neutrophil degranulation and antifungal killing. Cxcr1-/- mouse generation and systemic candidiasis model; survival, organ fungal burden, renal function, neutrophil trafficking and degranulation assays; human genetic variant (CXCR1-T276) functional analysis in patient neutrophils Science translational medicine High 26791948
2016 CXCR1 regulates pulmonary anti-Pseudomonas neutrophil responses by modulating reactive oxygen species production and Toll-like receptor 5 expression, functioning as a non-canonical chemokine receptor in innate host defense. Airway P. aeruginosa infection model in mice; in vivo bioluminescence imaging; neutrophil effector response assays; TLR5 expression analysis; human airway samples Journal of innate immunity Medium 26950764
2010 CXCR1 blockade in breast cancer depletes cancer stem cells and induces massive apoptosis of bulk tumor cells via FASL/FAS signaling; the mechanism involves the FAK/AKT/FOXO3A pathway; the CXCR1-specific inhibitor repertaxin recapitulates these effects in human breast cancer xenografts. CXCR1-specific blocking antibody and repertaxin treatment of breast cancer cell lines; ALDH/flow cytometry for CSC quantification; FASL/FAS apoptosis assays; FAK/AKT/FOXO3A pathway analysis; NOD/SCID xenograft models The Journal of clinical investigation High 20051626
2007 HIF-1 and NF-κB bind to the CXCR1 promoter and transcriptionally upregulate CXCR1 expression in response to hypoxia in prostate cancer cells; siRNA knockdown of HIF-1 or NF-κB, a HIF-1 dominant-negative, and pharmacological inhibitors all abrogate hypoxia-induced CXCR1 transcription. Chromatin immunoprecipitation (ChIP) demonstrating HIF-1 and NF-κB binding to CXCR1; siRNA knockdown; HIF-1 dominant-negative construct; pharmacological inhibitors; RT-PCR and immunoblotting in PC3 prostate cancer cells Oncogene High 17533374
2006 Mouse CXCR1 (mCXCR1) is a functional receptor predominantly engaged by mouse GCP-2/CXCL6 and human IL-8/CXCL8 (but not by CXCR2-selective ligands ENA-78, NAP-2, GRO-α/β/γ, or CINC-1-3), as demonstrated by ligand binding, GTPγS exchange stimulation, and chemotaxis of mCXCR1-transfected cells. Cloning of mCXCR1 cDNA; radioligand binding assays; [35S]-GTPγS exchange assay; chemotaxis of mCXCR1-transfected cells; ligand panel screening The Journal of biological chemistry High 17197447
2002 Phagocytosis-induced downregulation of CXCR1 (and CXCR2) on human neutrophils occurs via metalloproteinase-dependent proteolytic degradation at the cell surface (not via internalization), as the metalloproteinase inhibitor 1,10-phenanthroline prevents reduction and confocal microscopy shows no internalization. Flow cytometry of CXCR1/CXCR2 surface expression after phagocytosis of opsonized yeast; metalloproteinase inhibitor treatment; confocal microscopy; Ca2+ response assays; RT-PCR for mRNA levels Blood Medium 12239185
2002 CXCR1 internalization and recycling require actin-related kinase activity (sensitive to wortmannin); when both CXCR1 and CXCR2 are co-expressed, CXCR1 internalization is decreased compared to cells expressing only CXCR1, indicating receptor crosstalk during internalization. HEK293 transfectants with wild-type and chimeric/mutant CXCR1/CXCR2 constructs; wortmannin treatment; internalization and recycling assays; actin organization analysis European journal of immunology Medium 12442335
2006 CXCL8-induced chemotaxis via CXCR1 and CXCR2 is mediated through a pathway involving PI3K-dependent Cbl phosphorylation and Akt activation; Cbl overexpression (wild-type and G306E mutant, but not the RING-finger 70Z mutant) inhibits chemotaxis; kinase-dead Akt decreases both CXCL8-induced chemotaxis and Cbl phosphorylation; proteasome inhibitors block CXCR1/CXCR2 internalization. Cbl and Akt overexpression/dominant-negative in CXCR1/CXCR2-expressing L1.2 cells and human neutrophils; PI3K inhibitor LY294002; tyrphostin A9; proteasome inhibitors; co-immunoprecipitation of p85/Cbl; internalization assays International immunology Medium 16798838
2016 CXCR1 interacts specifically with accessory proteins REEP5 and REEP6 (CXCR2 does not); REEP5/6 are required for ligand-stimulated CXCR1 endocytosis and β-arrestin2 intracellular clustering but not for baseline CXCR1 membrane expression; REEP5/6 depletion impairs IL-8-stimulated ERK phosphorylation and actin polymerization downstream of CXCR1. Co-immunoprecipitation of CXCR1 with REEP5/6; overexpression and siRNA knockdown of REEP5/6; receptor internalization assays; β-arrestin2 clustering by immunofluorescence; ERK phosphorylation and actin polymerization assays; A549 xenograft model Scientific reports Medium 27966653
1993 The high-affinity IL-8 receptor gene (CXCR1/IL8RA) maps to chromosomal region 2q33-q36 and contains an intron in the 5' untranslated region; a pseudogene for the low-affinity IL-8 receptor (IL8RBP) was identified at a nearby locus. PCR-based cloning from genomic DNA; Southern blotting; in situ hybridization mapping to chromosome 2q33-q36; cDNA-genomic sequence comparison Genomics Medium 8486366
2017 In zebrafish, cxcl8/cxcr1 signaling (expressed in endothelial cells) positively regulates HSPC colonization by increasing HSPC-endothelial 'cuddling', HSPC residency time, and mitotic rate in the caudal hematopoietic tissue; enhanced cxcr1 signaling increases CHT volume and induces cxcl12a expression; cxcr1 acts hematopoietic stem cell-nonautonomously to improve donor HSPC engraftment in parabiotic zebrafish. Single-cell tracking of fluorescent HSPCs in zebrafish CHT; cxcr1 gain/loss-of-function; parabiotic zebrafish engraftment assay; cxcl12a expression analysis The Journal of experimental medicine Medium 28351983
2016 CXCR1 (but not CXCR2) deficiency in hepatocytes reduces exosome release and abolishes packaging of neutral ceramidase and sphingosine kinase into exosomes, eliminating the hepatocyte proliferative effect of these exosomes; CXCR2 deficiency increases exosome release through elevated neutral sphingomyelinase (Nsm) activity and ceramide production. CXCR1-/- and CXCR2-/- hepatocytes; exosome quantification; neutral sphingomyelinase activity assay; ceramide measurement; hepatocyte proliferation assay with conditioned exosomes PloS one Medium 27551720
2018 Natural posttranslational modifications of CXCL8 (N-terminal truncation to CXCL8(6-77) and citrullination to [Cit5]CXCL8) moderately enhance CXCR1 internalization and Gαi-dependent signaling, and increase β-arrestin 1 and 2 recruitment to CXCR1, without shifting the Gαi vs. β-arrestin signaling bias. Chemically synthesized CXCL8 variants; internalization assays with human neutrophils; Gαi-dependent signaling (HTRF); β-arrestin 1 and 2 recruitment assays to CXCR1 and CXCR2 International journal of molecular sciences Medium 30486423
2012 HIV-1 matrix protein p17 binds CXCR1 (and CXCR2) on endothelial cells with high affinity and promotes capillary-like structure formation via ERK/Akt signaling; p17 is internalized into endothelial cell nuclei through receptor-mediated endocytosis. High-affinity binding assays of p17 to CXCR2 and CXCR1 on endothelial cells; tube formation assay with blocking antibodies; ERK/Akt signaling analysis; ex vivo and in vivo angiogenesis models; confocal microscopy of p17 nuclear localization Proceedings of the National Academy of Sciences of the United States of America Medium 22904195
2009 CMV UL146-encoded vCXCL1 acts as a selective agonist of both CXCR1 and CXCR2 (affinities 44 nM and 5.6 nM respectively), activating calcium mobilization, phosphatidylinositol turnover, and chemotaxis, while not activating or blocking any of 16 other human chemokine receptors. Competition radioligand binding against CXCR1 and CXCR2; calcium mobilization; inositol triphosphate assay; chemotaxis assay in CHO, 300.19, COS7, and L1.2 cells expressing CXCR1 or CXCR2; panel of 18 chemokine receptor transfectants The Journal of biological chemistry High 20044480
2023 CXCR1 drives dendritic cell-dependent inflammation through a positive feedback loop involving CXCL5/CXCR1/HIF-1α signaling that directly regulates IL-6 and IL-12p70 production; DC-specific CXCR1 deletion suppresses inflammatory cytokine secretion and ameliorates EAE and LPS-induced ARDS. CXCR1 global and DC-specific knockout mice; EAE and ARDS models; antibody neutralization of CXCL5; cytokine ELISA; HIF-1α pathway analysis in DCs Cell death & disease Medium 37709757

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 CXCR1 and CXCR2 Chemokine Receptor Agonists Produced by Tumors Induce Neutrophil Extracellular Traps that Interfere with Immune Cytotoxicity. Immunity 655 32289253
2017 Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases. Theranostics 620 28529637
2010 CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. The Journal of clinical investigation 593 20051626
2016 The CXCL8-CXCR1/2 pathways in cancer. Cytokine & growth factor reviews 523 27578214
2019 CXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors. Nature communications 326 31488817
2019 Inhibition of MDSC Trafficking with SX-682, a CXCR1/2 Inhibitor, Enhances NK-Cell Immunotherapy in Head and Neck Cancer Models. Clinical cancer research : an official journal of the American Association for Cancer Research 240 31848188
2001 IL-8 activates endothelial cell CXCR1 and CXCR2 through Rho and Rac signaling pathways. American journal of physiology. Lung cellular and molecular physiology 224 11350788
2007 HIF-1 and NF-kappaB-mediated upregulation of CXCR1 and CXCR2 expression promotes cell survival in hypoxic prostate cancer cells. Oncogene 176 17533374
2006 Murine CXCR1 is a functional receptor for GCP-2/CXCL6 and interleukin-8/CXCL8. The Journal of biological chemistry 175 17197447
1999 Expression and function of the chemokine receptors CXCR1 and CXCR2 in sepsis. Journal of immunology (Baltimore, Md. : 1950) 174 9973513
2009 Differential activation and regulation of CXCR1 and CXCR2 by CXCL8 monomer and dimer. Journal of immunology (Baltimore, Md. : 1950) 159 19667085
2012 CXCR1/2 inhibition enhances pancreatic islet survival after transplantation. The Journal of clinical investigation 124 22996693
2005 The CXCR1 and CXCR2 receptors form constitutive homo- and heterodimers selectively and with equal apparent affinities. The Journal of biological chemistry 107 15946947
1999 beta-arrestins regulate interleukin-8-induced CXCR1 internalization. The Journal of biological chemistry 106 10347185
2021 Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy. Molecules (Basel, Switzerland) 101 35011369
2009 CXCR1 and CXCR2 enhances human melanoma tumourigenesis, growth and invasion. British journal of cancer 95 19401689
2022 Targeting T cell checkpoints 41BB and LAG3 and myeloid cell CXCR1/CXCR2 results in antitumor immunity and durable response in pancreatic cancer. Nature cancer 94 36585453
2004 Ligand selectivity and affinity of chemokine receptor CXCR1. Role of N-terminal domain. The Journal of biological chemistry 94 15133028
2021 Combined Inhibition of SHP2 and CXCR1/2 Promotes Antitumor T-cell Response in NSCLC. Cancer discovery 92 34353854
2006 Distinct expression of CXCL8 and its receptors CXCR1 and CXCR2 and their association with vessel density and aggressiveness in malignant melanoma. American journal of clinical pathology 91 16393674
2021 Reduction of NETosis by targeting CXCR1/2 reduces thrombosis, lung injury, and mortality in experimental human and murine sepsis. British journal of anaesthesia 88 34893315
2018 IL-8/CXCR1/2 signalling promotes tumor cell proliferation, invasion and vascular mimicry in glioblastoma. Journal of biomedical science 84 30086759
2012 HIV-1 matrix protein p17 promotes angiogenesis via chemokine receptors CXCR1 and CXCR2. Proceedings of the National Academy of Sciences of the United States of America 83 22904195
2001 Expression of the chemokine receptors CXCR1 and CXCR2 in rat oligodendroglial cells. Brain research. Developmental brain research 78 11356265
2014 CXCR1/2 inhibition blocks and reverses type 1 diabetes in mice. Diabetes 77 25315007
2003 Expression of CXCR1 and CXCR2 receptors in malignant melanoma with different metastatic potential and their role in interleukin-8 (CXCL-8)-mediated modulation of metastatic phenotype. Clinical & experimental metastasis 76 14713106
1999 Differential modes of regulation of cxc chemokine-induced internalization and recycling of human CXCR1 and CXCR2. Cytokine 74 10623425
2016 CXCR1-mediated neutrophil degranulation and fungal killing promote Candida clearance and host survival. Science translational medicine 72 26791948
2004 Cutting edge: expression of chemokine receptor CXCR1 on human effector CD8+ T cells. Journal of immunology (Baltimore, Md. : 1950) 72 15294933
2020 Simultaneous inhibition of CXCR1/2, TGF-β, and PD-L1 remodels the tumor and its microenvironment to drive antitumor immunity. Journal for immunotherapy of cancer 71 32188703
2011 CXCR1 and CXCR2 silencing modulates CXCL8-dependent endothelial cell proliferation, migration and capillary-like structure formation. Microvascular research 69 21749879
1998 Expression and functional activity of the IL-8 receptor type CXCR1 and CXCR2 on human mast cells. Journal of immunology (Baltimore, Md. : 1950) 69 9725262
2012 Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor. British journal of pharmacology 66 21718305
2015 Targeting CXCR1 on breast cancer stem cells: signaling pathways and clinical application modelling. Oncotarget 62 26517518
2008 TLR- and CXCR1-dependent innate immunity: insights into the genetics of urinary tract infections. European journal of clinical investigation 61 18826477
2009 The cytomegalovirus UL146 gene product vCXCL1 targets both CXCR1 and CXCR2 as an agonist. The Journal of biological chemistry 60 20044480
2007 Interleukin-8 and CXCR1 receptor functional polymorphisms and susceptibility to acute pyelonephritis. The Journal of urology 59 17296422
2016 IL-8 promotes HNSCC progression on CXCR1/2-meidated NOD1/RIP2 signaling pathway. Oncotarget 54 27557518
2005 A homolog of the human chemokine receptor CXCR1 is expressed in the mouse. Molecular immunology 54 16084593
2005 Cloning and characterization of mouse homolog of the CXC chemokine receptor CXCR1. Cytokine 53 15967374
2008 Expression of CXCL8, CXCR1, and CXCR2 in neurons and glial cells of the human and rabbit retina. Investigative ophthalmology & visual science 51 18552386
2022 Targeting CXCR1 and CXCR2 receptors in cardiovascular diseases. Pharmacology & therapeutics 50 35908611
2010 Targeting CXCR1/CXCR2 receptor antagonism in malignant melanoma. Expert opinion on therapeutic targets 50 20230195
2017 CXCR1/2 pathways in paclitaxel-induced neuropathic pain. Oncotarget 48 28423567
2010 Small interfering RNA-mediated CXCR1 or CXCR2 knock-down inhibits melanoma tumor growth and invasion. International journal of cancer 48 19585580
2021 The IL-8-CXCR1/2 axis contributes to diabetic kidney disease. Metabolism: clinical and experimental 46 34097917
2023 Therapeutic inhibition of CXCR1/2: where do we stand? Internal and emergency medicine 45 37249756
2007 CXCR1 and CXCR2 activation and regulation. Role of aspartate 199 of the second extracellular loop of CXCR2 in CXCL8-mediated rapid receptor internalization. The Journal of biological chemistry 45 17204468
2021 An updated review on the role of the CXCL8-CXCR1/2 axis in the progression and metastasis of breast cancer. Molecular biology reports 44 34426905
2010 CXCR1 and SLC11A1 polymorphisms affect susceptibility to cutaneous leishmaniasis in Brazil: a case-control and family-based study. BMC medical genetics 44 20089160
2009 Dynamic regulation of CXCR1 and CXCR2 homo- and heterodimers. Journal of immunology (Baltimore, Md. : 1950) 44 19890050
2017 CXCR1 remodels the vascular niche to promote hematopoietic stem and progenitor cell engraftment. The Journal of experimental medicine 43 28351983
2011 Local and global dynamics of the G protein-coupled receptor CXCR1. Biochemistry 43 21323370
2011 Decreased CXCR1 and CXCR2 expression on neutrophils in anti-neutrophil cytoplasmic autoantibody-associated vasculitides potentially increases neutrophil adhesion and impairs migration. Arthritis research & therapy 42 22152684
2019 Activation of CXCL6/CXCR1/2 Axis Promotes the Growth and Metastasis of Osteosarcoma Cells in vitro and in vivo. Frontiers in pharmacology 41 30984000
2019 New CXCR1/CXCR2 inhibitors represent an effective treatment for kidney or head and neck cancers sensitive or refractory to reference treatments. Theranostics 38 31410218
2004 Human T lymphocytes and mast cells differentially express and regulate extra- and intracellular CXCR1 and CXCR2. Experimental dermatology 38 15265017
2002 Phagocytosing neutrophils down-regulate the expression of chemokine receptors CXCR1 and CXCR2. Blood 38 12239185
2020 Structural Insights Into How Proteoglycans Determine Chemokine-CXCR1/CXCR2 Interactions: Progress and Challenges. Frontiers in immunology 37 32391006
2019 IL-8 and CXCR1 expression is associated with cancer stem cell-like properties of clear cell renal cancer. The Journal of pathology 37 30883740
2006 Expression of the chemokine receptor CXCR1 in human glomerular diseases. Kidney international 37 16541017
2005 Cross-desensitization among CXCR1, CXCR2, and CCR5: role of protein kinase C-epsilon. Journal of immunology (Baltimore, Md. : 1950) 37 15905535
2019 Interleukin-8 promotes cell migration via CXCR1 and CXCR2 in liver cancer. Oncology letters 36 31516616
2014 High expression of GPER1, EGFR and CXCR1 is associated with lymph node metastasis in papillary thyroid carcinoma. International journal of clinical and experimental pathology 35 25031742
2019 Disrupting Inflammation-Associated CXCL8-CXCR1 Signaling Inhibits Tumorigenicity Initiated by Sporadic- and Colitis-Colon Cancer Stem Cells. Neoplasia (New York, N.Y.) 34 30738331
2019 Sinomenine inhibits osteolysis in breast cancer by reducing IL-8/CXCR1 and c-Fos/NFATc1 signaling. Pharmacological research 34 30797069
2014 The chemokine receptors CXCR1 and CXCR2 regulate oral cancer cell behaviour. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 34 24965032
2015 CXCR1 knockdown improves the sensitivity of osteosarcoma to cisplatin. Cancer letters 33 26391645
2007 Identification of single nucleotide polymorphisms in the bovine CCL2, IL8, CCR2 and IL8RA genes and their association with health and production in Canadian Holsteins. Animal genetics 33 17433017
2005 Expression of interleukin-8 receptors (CXCR1 and CXCR2) in premenopausal women with recurrent urinary tract infections. Clinical and diagnostic laboratory immunology 33 16339057
2020 KLF2 regulates neutrophil migration by modulating CXCR1 and CXCR2 in asthma. Biochimica et biophysica acta. Molecular basis of disease 32 32800946
2016 Combined inhibition of IL1, CXCR1/2, and TGFβ signaling pathways modulates in-vivo resistance to anti-VEGF treatment. Anti-cancer drugs 32 26473526
2010 CXCR1 and CXCR2 are novel mechano-sensors mediating laminar shear stress-induced endothelial cell migration. Cytokine 32 21036625
2016 Chemokine Receptors, CXCR1 and CXCR2, Differentially Regulate Exosome Release in Hepatocytes. PloS one 29 27551720
2006 Cbl and Akt regulate CXCL8-induced and CXCR1- and CXCR2-mediated chemotaxis. International immunology 28 16798838
2016 The accessory proteins REEP5 and REEP6 refine CXCR1-mediated cellular responses and lung cancer progression. Scientific reports 27 27966653
2023 Small molecule antagonist of CXCR2 and CXCR1 inhibits tumor growth, angiogenesis, and metastasis in pancreatic cancer. Cancer letters 26 37062329
2016 CXCR1 Regulates Pulmonary Anti-Pseudomonas Host Defense. Journal of innate immunity 26 26950764
2015 The CXCR1/2 Pathway: Involvement in Diabetes Pathophysiology and Potential Target for T1D Interventions. Current diabetes reports 26 26275440
2004 Downregulation of CXCR1 and CXCR2 expression on human neutrophils by Helicobacter pylori: a new pathomechanism in H. pylori infection? Infection and immunity 26 15557597
2023 The Role of CXCR1, CXCR2, CXCR3, CXCR5, and CXCR6 Ligands in Molecular Cancer Processes and Clinical Aspects of Acute Myeloid Leukemia (AML). Cancers 25 37760523
2018 Role of CXCR1 and Interleukin-8 in Methamphetamine-Induced Neuronal Apoptosis. Frontiers in cellular neuroscience 25 30123110
2021 CXCR1 correlates to poor outcomes of EGFR-TKI against advanced non-small cell lung cancer by activating chemokine and JAK/STAT pathway. Pulmonary pharmacology & therapeutics 23 33582208
2012 Genetic variations of interleukin-8, CXCR1 and CXCR2 genes and risk of acute pyelonephritis in children. International journal of immunogenetics 23 22325052
2011 CXCR1 and CXCR2 haplotypes synergistically modulate cystic fibrosis lung disease. The European respiratory journal 23 22088968
1993 The high-affinity interleukin 8 receptor gene (IL8RA) maps to the 2q33-q36 region of the human genome: cloning of a pseudogene (IL8RBP) for the low-affinity receptor. Genomics 23 8486366
2021 Conformational plasticity and dynamic interactions of the N-terminal domain of the chemokine receptor CXCR1. PLoS computational biology 22 34014914
2022 The CXCR1/CXCR2 Inhibitor Reparixin Alters the Development of Myelofibrosis in the Gata1 low Mice. Frontiers in oncology 21 35392239
2019 The antagonist of CXCR1 and CXCR2 protects db/db mice from metabolic diseases through modulating inflammation. American journal of physiology. Endocrinology and metabolism 21 31573846
2002 Expression of the interleukin-8 receptors CXCR1 and CXCR2 on cord-blood-derived cultured human mast cells. International archives of allergy and immunology 21 12065915
2021 MiR-144-induced KLF2 inhibition and NF-kappaB/CXCR1 activation promote neutrophil extracellular trap-induced transfusion-related acute lung injury. Journal of cellular and molecular medicine 19 34120407
2020 MMP9, CXCR1, TLR6, and MPO participant in the progression of coronary artery disease. Journal of cellular physiology 19 32052443
2004 CXCR1+CD4+ T cells in human allergic disease. Journal of immunology (Baltimore, Md. : 1950) 19 14688334
2002 Intracellular trafficking of human CXCR1 and CXCR2: regulation by receptor domains and actin-related kinases. European journal of immunology 19 12442335
2024 A narrative review of chemokine receptors CXCR1 and CXCR2 and their role in acute respiratory distress syndrome. European respiratory review : an official journal of the European Respiratory Society 18 39048127
2022 CXCR1 and its downstream NF-κB inflammation signaling pathway as a key target of Guanxinning injection for myocardial ischemia/reperfusion injury. Frontiers in immunology 18 36325326
2018 Differential Effects of Posttranslational Modifications of CXCL8/Interleukin-8 on CXCR1 and CXCR2 Internalization and Signaling Properties. International journal of molecular sciences 18 30486423
2011 Elevated expression of the interleukin-8 receptors CXCR1 and CXCR2 in peripheral blood cells in obstructive coronary artery disease. Coronary artery disease 18 21915051
2023 CXCR1 drives the pathogenesis of EAE and ARDS via boosting dendritic cells-dependent inflammation. Cell death & disease 17 37709757
2022 Genetic Variant of CXCR1 (rs2234671) Associates with Clinical Outcome in Perihilar Cholangiocarcinoma. Liver cancer 17 35634429

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