Affinage

CXCR1

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

Length
350 aa
Mass
39.8 kDa
Annotated
2026-04-28
100 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CXCR1 is a Gi-coupled chemokine receptor that selectively binds monomeric IL-8/CXCL8 through a two-site mechanism involving its N-terminal domain and transmembrane regions, activating downstream ERK1/2, AKT, phospholipase C, and Ca²⁺ signaling cascades to drive neutrophil chemotaxis, degranulation, and transepithelial migration (PMID:15133028, PMID:15252057, PMID:11046063, PMID:26791948). Ligand-induced receptor desensitization requires GRK2-mediated C-tail phosphorylation at six key sites, which recruits β-arrestin and triggers clathrin/dynamin-dependent internalization, while the DRY motif residue D134 is essential for G-protein coupling and ligand binding (PMID:10347185, PMID:10623425, PMID:12626541, PMID:25834784). CXCR1 forms homo- and heterodimers with CXCR2 whose balance is dynamically regulated by CXCL8, and it cross-phosphorylates CCR1 but is itself resistant to CCR1-mediated cross-desensitization, establishing an asymmetric chemokine receptor signaling hierarchy (PMID:19890050, PMID:10734056). Beyond neutrophils, CXCR1 mediates neuronal Ca²⁺ channel modulation via Giα, drives dendritic cell inflammatory cytokine production through a CXCL5/HIF-1α feedback loop, regulates breast cancer stem cell survival via FAK/AKT/FOXO3A, and its proteolytic cleavage in cystic fibrosis airways disables neutrophil bactericidal capacity (PMID:11553670, PMID:37709757, PMID:20051626, PMID:18059279).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1998 High

    Establishing that CXCR1 surface expression is regulated independently of its own ligand: LPS down-modulates CXCR1 on neutrophils through an agonist-independent, tyrosine kinase (p72syk)-dependent mechanism, revealing that receptor availability is controlled by innate immune signals beyond IL-8.

    Evidence Flow cytometry on human neutrophils with tyrosine kinase inhibitors and p72syk phosphorylation western blot

    PMID:9712063

    Open questions at the time
    • Identity of kinases downstream of p72syk mediating receptor loss not determined
    • Whether LPS causes receptor internalization vs. shedding vs. transcriptional suppression not fully resolved
  2. 1999 High

    Defining the endocytic machinery for CXCR1: β-arrestin recruitment, GRK2-mediated phosphorylation, and dynamin/clathrin-dependent internalization were shown to be required, and the six C-terminal phosphorylation sites were identified as the primary internalization determinant—distinguishing CXCR1 from CXCR2 whose internalization relies on a membrane-proximal domain.

    Evidence Dominant-negative β-arrestin 1-V53D and dynamin K44A mutants in HEK293 and RBL-2H3 cells; C-tail truncation and phosphorylation-site mutants with recycling assays

    PMID:10347185 PMID:10623425

    Open questions at the time
    • Specific GRK2 phosphorylation sites within the six-site cluster not mapped individually
    • Whether other GRKs contribute in primary neutrophils not addressed
  3. 2000 High

    Revealing asymmetric cross-talk between chemokine receptors: IL-8/CXCR1 stimulation cross-phosphorylates and desensitizes CCR1, but CCR1 activation cannot reciprocally cross-desensitize CXCR1, establishing a signaling hierarchy among co-expressed chemokine receptors.

    Evidence RBL-2H3 cells co-expressing CCR1 with CXCR1 or CXCR2; receptor phosphorylation, GTPase, and Ca²⁺ assays with phosphorylation-deficient mutant controls

    PMID:10734056

    Open questions at the time
    • Kinase responsible for heterologous CXCR1→CCR1 phosphorylation not identified
    • Relevance of this hierarchy in primary neutrophils co-expressing multiple receptors not tested
  4. 2001 High

    Identifying CXCR1's non-redundant role in transepithelial neutrophil migration: antibody blockade and receptor knockout showed that CXCR1 (not CXCR2) on uroepithelial cells is required for neutrophil transmigration across infected mucosal barriers, linking CXCR1 to mucosal innate defense.

    Evidence Anti-CXCR1/CXCR2 blocking antibodies in epithelial migration assays; IL-8 receptor knockout mice with experimental UTI

    PMID:11046063

    Open questions at the time
    • Whether epithelial CXCR1 acts by transcytosing IL-8 or by direct signaling in epithelial cells not resolved
    • Contribution of CXCR1 on other mucosal surfaces not tested
  5. 2001 High

    Demonstrating CXCR1 function outside the immune system: IL-8 acting through CXCR1 in cholinergic septal neurons closes L- and N-type Ca²⁺ channels via Giα1/Giα2, establishing that CXCR1 modulates neuronal excitability.

    Evidence Whole-cell patch clamp with single-cell RT-PCR from rat septal neurons; pharmacological G-protein subtype dissection

    PMID:11553670

    Open questions at the time
    • Physiological role of CXCR1 in brain function not defined
    • Whether neuronal CXCR1 undergoes the same internalization/desensitization as in immune cells unknown
  6. 2001 Medium

    Mapping the intracellular domain architecture for G-protein signaling: the second intracellular loop of CXCR1 was identified as the major determinant of Gi-coupled ERK1/2 activation and chemotaxis through domain-swap chimeras with CXCR5.

    Evidence CXCR1/CXCR5 chimeric receptors assayed for pertussis toxin sensitivity, Ca²⁺ flux, ERK1/2 phosphorylation, and chemotaxis

    PMID:11688722

    Open questions at the time
    • Specific residues within ICL2 mediating Gi coupling not identified
    • Single-lab chimeric study without independent replication
  7. 2003 High

    Dissecting the functional consequences of C-tail phosphorylation: phosphorylation-deficient mutants showed that C-tail phosphorylation is required for β-arrestin translocation and internalization but dispensable for—and actually inhibitory toward—phosphoinositide hydrolysis, exocytosis, and chemotaxis, uncoupling desensitization from effector function.

    Evidence Wild-type, chimeric, and phosphorylation-deficient CXCR1/CXCR2 mutants in RBL-2H3 cells with comprehensive signaling readouts

    PMID:12626541

    Open questions at the time
    • Whether constitutive (non-ligand-dependent) phosphorylation occurs and affects basal trafficking not tested
    • Role of individual phosphosites in graded β-arrestin recruitment not resolved
  8. 2004 High

    Resolving the structural basis of ligand selectivity: NMR and biophysical studies showed that the CXCR1 N-terminal domain selectively binds the IL-8 monomer (not dimer) in a membrane-dependent conformation, with ITC quantifying binding affinity and establishing that IL-8 dimerization is a negative regulator of receptor engagement.

    Evidence NMR in detergent micelles; ITC and sedimentation equilibrium comparing IL-8 monomer vs. dimer binding to CXCR1 N-domain peptide

    PMID:15133028 PMID:15252057

    Open questions at the time
    • Full-length receptor–ligand structure not determined
    • How the N-domain binding step couples to TM domain activation (two-site mechanism) not structurally resolved
  9. 2004 High

    Establishing the agonist concentration threshold for internalization in primary neutrophils: receptor endocytosis requires ~10-fold higher IL-8 concentrations than chemotaxis and Ca²⁺ flux, and both receptors are excluded from lipid rafts, clarifying that internalization is a high-dose response separable from migration.

    Evidence Dose-response internalization, Ca²⁺ flux, and sucrose gradient fractionation in primary human neutrophils with clathrin/dynamin pathway inhibitors

    PMID:15028716

    Open questions at the time
    • Whether sustained low-dose exposure eventually drives internalization not assessed
    • Mechanism of lipid raft exclusion not defined
  10. 2005 High

    Identifying the transmembrane allosteric binding pocket: repertaxin was shown to inhibit CXCR1 non-competitively by binding within the transmembrane region, validated by alanine scanning mutagenesis and photoaffinity labeling.

    Evidence Molecular modeling; systematic alanine mutagenesis of CXCR1 TM residues; photoaffinity labeling

    PMID:15974585

    Open questions at the time
    • Atomic-resolution structure of the repertaxin–CXCR1 complex not available
    • Whether TM allosteric site is conserved across species not tested
  11. 2007 High

    Linking CXCR1 proteolysis to impaired host defense in cystic fibrosis: neutrophil-surface CXCR1 cleavage by airway proteases abolished bacterial killing capacity (which required CXCR1 but not CXCR2), and shed CXCR1 fragments amplified inflammation via TLR2; α1-antitrypsin inhalation restored CXCR1 and bacterial killing in CF patients.

    Evidence Protease-treated neutrophils with bacterial killing assays; TLR2 stimulation by CXCR1 fragments; in vivo α1-antitrypsin inhalation in CF patients

    PMID:18059279

    Open questions at the time
    • Specific protease(s) cleaving CXCR1 in CF airways not definitively identified
    • Mechanism by which CXCR1 (but not CXCR2) supports bacterial killing not molecularly resolved
  12. 2009 High

    Demonstrating receptor dimerization dynamics: FRET in primary neutrophils showed that CXCR1 forms homo- and heterodimers with CXCR2; CXCL8 stabilizes homodimers while remodeling heterodimeric complexes, indicating that oligomeric state is a regulatable signaling parameter.

    Evidence FRET measurements in human neutrophils and transfected cell lines under varying receptor expression and ligand conditions

    PMID:19890050

    Open questions at the time
    • Functional consequence of homodimer vs. heterodimer signaling not determined
    • Structural basis of dimer interface unknown
  13. 2010 High

    Establishing CXCR1 as a breast cancer stem cell vulnerability: CXCR1 blockade depleted CSCs and triggered bystander apoptosis in bulk tumor cells through FASL/FAS signaling downstream of FAK/AKT/FOXO3A, positioning CXCR1 as a therapeutic target in breast cancer.

    Evidence CXCR1 blocking antibody and repertaxin in vitro and in human breast cancer xenografts; FAK/AKT/FOXO3A pathway inhibitor dissection

    PMID:20051626

    Open questions at the time
    • Whether CXCR1 marks a functionally distinct CSC subset or is universally expressed on CSCs unclear
    • Mechanism linking CXCR1 blockade specifically to FASL upregulation not fully dissected
  14. 2015 High

    Confirming the essential DRY motif and identifying a TM6 activation hotspot: D134 mutations abolished both ligand binding and signaling, while M241/F251 mutations on TM6 generated constitutive activity, mapping the structural requirements for CXCR1 activation.

    Evidence Site-directed mutagenesis with radioligand binding, Ca²⁺ mobilization, and G15 activation assays in transfected cells

    PMID:25834784

    Open questions at the time
    • No full active-state structure to contextualize the TM6 mutations
    • Whether TM6 constitutive-activity mutants signal through Gi or only promiscuous G15 not clarified
  15. 2015 High

    Demonstrating CXCR1's non-redundant role in antifungal defense through degranulation: Cxcr1−/− mice had impaired neutrophil degranulation (not chemotaxis) and increased mortality in systemic candidiasis, and the human CXCR1-T276 variant recapitulated this degranulation defect, linking a specific cellular function to host antifungal immunity.

    Evidence Cxcr1−/− mouse systemic candidiasis model; neutrophil degranulation and trafficking assays; human CXCR1-T276 variant functional studies and genetic association

    PMID:26791948

    Open questions at the time
    • Signaling pathway connecting CXCR1 specifically to degranulation machinery not defined
    • CXCR1-T276 patient cohort limited; broader replication needed
  16. 2016 Medium

    Identifying REEP5/REEP6 as CXCR1-specific accessory proteins: Co-IP showed these ER-shaping proteins interact selectively with CXCR1, facilitating its ligand-stimulated endocytosis, β-arrestin2 clustering, and downstream ERK signaling rather than surface trafficking.

    Evidence Co-immunoprecipitation; siRNA knockdown and overexpression of REEP5/6; CXCR1 internalization, β-arrestin2 clustering, and ERK phosphorylation assays

    PMID:27966653

    Open questions at the time
    • Reciprocal Co-IP and endogenous interaction not confirmed
    • Structural basis of REEP5/6 selectivity for CXCR1 over CXCR2 unknown
    • Single-lab finding not independently replicated
  17. 2023 Medium

    Extending CXCR1's role to dendritic cell biology: DC-specific CXCR1 knockout revealed a CXCL5/CXCR1/HIF-1α positive feedback loop driving IL-6/IL-12p70 production in inflammatory disease models (EAE, ARDS), expanding CXCR1 function beyond neutrophils.

    Evidence DC-specific CXCR1 knockout mice in EAE and LPS-ARDS models; cytokine profiling; HIF-1α pathway analysis; CXCL5 neutralization

    PMID:37709757

    Open questions at the time
    • Whether HIF-1α is a direct transcriptional target of CXCR1 signaling or secondary to metabolic changes not resolved
    • Single-lab finding; independent replication in other DC-driven disease models needed

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of CXCR1 in complex with monomeric IL-8 (or other ligands) and coupled G-protein has not been determined; the molecular basis for CXCR1's selective coupling to degranulation (but not chemotaxis) pathways, the identity of the protease(s) cleaving CXCR1 in disease airways, and the functional significance of CXCR1/CXCR2 dimer stoichiometry in vivo remain open questions.
  • No full-length CXCR1–IL-8–Gi cryo-EM or crystal structure
  • Signaling branch point distinguishing degranulation from chemotaxis downstream of CXCR1 unknown
  • CXCR1/CXCR2 heterodimer functional consequences in vivo undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005768 endosome 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 4 R-HSA-9609507 Protein localization 4
Partners
ARRB1ARRB2CCR1CXCL8CXCR2GRK2REEP5REEP6
Complex memberships
CXCR1 homodimerCXCR1/CXCR2 heterodimer

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 β-arrestins regulate IL-8-induced CXCR1 internalization: GRK2 and β-arrestin proteins are required for CXCR1 internalization in HEK 293 cells; a dominant-negative β-arrestin 1-V53D mutant blocks CXCR1 internalization; dynamin is also required; internalization occurs via clathrin-coated vesicles. CXCR1-GFP constructs transiently expressed in HEK 293 and RBL-2H3 cells; dominant-negative mutants (β-arrestin 1-V53D, dynamin I-K44A); co-localization with transferrin in endosomes The Journal of biological chemistry High 10347185
1999 IL-8-induced internalization of CXCR1 is profoundly dependent on a carboxyl-terminal region containing six phosphorylation sites, whereas CXCR2 internalization is primarily regulated by a membrane-proximal domain that lacks phosphorylation sites; both receptors recycle after ligand removal. HEK 293 cell transfectants expressing wild-type and carboxyl-tail mutants of CXCR1 and CXCR2; receptor internalization and recycling assays Cytokine High 10623425
1998 LPS down-modulates CXCR1 and CXCR2 expression on neutrophils through an agonist-independent, tyrosine kinase-dependent pathway involving p72syk hyperphosphorylation; tyrosine kinase inhibitors (genistein, herbimycin A) attenuate this down-modulation, whereas they have no effect on IL-8-induced receptor down-modulation. Flow cytometry of CXCR1/CXCR2 on human neutrophils; tyrosine kinase inhibitor experiments; ELISA for cytokines; western blot for p72syk phosphorylation Journal of immunology High 9712063
2003 Phosphorylation of the C-tails of CXCR1 and CXCR2 is required for β-arrestin translocation and receptor internalization; C-tail-deleted and phosphorylation-deficient mutants show greater phosphoinositide hydrolysis and exocytosis but diminished chemotaxis; receptor internalization is not required for chemotaxis. CXCR2 (but not CXCR1) undergoes rapid internalization that is not fully explained by C-tail phosphorylation alone. Wild-type, chimeric, phosphorylation-deficient, and C-tail deletion mutants of CXCR1/CXCR2 expressed in RBL-2H3 cells; receptor phosphorylation, desensitization, internalization, β-arrestin 2 translocation, and chemotaxis assays Journal of immunology High 12626541
2004 CXCR1 ligand selectivity is mediated by its N-terminal domain (N-domain): IL-8 binds the N-domain with higher affinity in membrane-mimicking micelles (~1 µM) than in solution (~20 µM); MGSA does not bind the N-domain in solution but binds in micelles (~3 µM); the entire N-domain interacts with the micelle in an extended fashion, with conformational restraint governing ligand-binding properties. NMR structural studies; ligand-binding in detergent micelles vs. solution; fluorescence and circular dichroism spectroscopy The Journal of biological chemistry High 15133028
2004 Only the IL-8 monomer (not the dimer) is competent to bind the CXCR1 N-terminal domain; IL-8 dimerization functions as a negative regulator for receptor binding and a positive regulator for glycosaminoglycan binding. Isothermal titration calorimetry and sedimentation equilibrium to measure IL-8 binding to the CXCR1 N-domain; comparison of native IL-8 vs. monomer/dimer The Journal of biological chemistry High 15252057
2004 Ligand-induced endocytosis of CXCR1 and CXCR2 in primary human neutrophils requires ~10-fold higher agonist concentrations than maximal chemotaxis and calcium flux; both receptors are excluded from Triton X-100-insoluble lipid rafts and internalized via a clathrin/rab5/dynamin-dependent pathway; receptor endocytosis is not required for chemotaxis. Primary human neutrophil receptor internalization assays; calcium flux measurements; sucrose density gradient fractionation (lipid raft analysis); clathrin/dynamin pathway inhibitor experiments The Journal of biological chemistry High 15028716
2005 Repertaxin (reparixin) acts as a noncompetitive CXCL8 inhibitor by interacting with a putative binding site in the transmembrane region of CXCR1; the binding model was confirmed by alanine scanning mutagenesis and photoaffinity labeling experiments. Molecular modeling; alanine scanning mutagenesis of CXCR1; photoaffinity labeling experiments Journal of medicinal chemistry High 15974585
2006 Murine CXCR1 (mCXCR1) is a functional receptor predominantly engaged by mouse GCP-2/CXCL6, human GCP-2, and IL-8/CXCL8, but not by CXCR2 ligands (ENA-78, NAP-2, GRO-α/β/γ); functional characterization via binding, GTPγS exchange stimulation, and chemotaxis of mCXCR1-transfected cells. Radioligand binding; GTPγS exchange assay; chemotaxis assay with transfected cells; RT-PCR for tissue distribution The Journal of biological chemistry High 17197447
2007 IL-8 promotes bacterial killing by neutrophils through CXCR1 but not CXCR2; proteolytic cleavage of CXCR1 on neutrophils in cystic fibrosis airways disables their bacterial-killing capacity; soluble glycosylated CXCR1 fragments stimulate IL-8 production in bronchial epithelial cells via TLR2; in vivo inhalation of α1-antitrypsin restored CXCR1 expression and bacterial killing. Protease treatment of neutrophils; functional bacterial killing assays; CXCR1 fragment identification and TLR2 stimulation assays; in vivo α1-antitrypsin inhalation study in CF patients Nature medicine High 18059279
2007 SCH527123 (Sch527123) is an allosteric antagonist of both CXCR1 and CXCR2, acting in an insurmountable (non-competitive) manner; it binds CXCR1 with Kd = 3.9 nM and CXCR2 with Kd = 0.049 nM; it inhibits CXCL1- and CXCL8-stimulated neutrophil chemotaxis and myeloperoxidase release without affecting C5a or fMLP responses. Radioligand binding ([³H]Sch527123); equilibrium and non-equilibrium binding analyses; GTPγS binding; neutrophil chemotaxis and MPO release assays; receptor selectivity panel The Journal of pharmacology and experimental therapeutics High 17496166
2009 CXCR1 and CXCR2 form homo- and heterodimers in human neutrophils and cell lines; CXCL8 alters heterodimeric complexes while stabilizing homodimers and promoting receptor internalization; receptor expression level and ligand activation regulate the balance between these oligomeric states. Fluorescence resonance energy transfer (FRET) in human neutrophils and transfected cell lines; receptor expression modulation experiments Journal of immunology High 19890050
2009 CMV UL146 gene product vCXCL1 acts as an agonist on both CXCR1 and CXCR2 (Kd = 44 nM and 5.6 nM, respectively), inducing calcium mobilization, phosphatidylinositol turnover, and chemotaxis via these receptors, but does not activate or block any other 16 human chemokine receptors. Competition binding against radiolabeled CXCL8; calcium mobilization assays; inositol triphosphate turnover; chemotaxis assays in CXCR1/CXCR2-expressing CHO, 300.19, COS7, and L1.2 cells The Journal of biological chemistry High 20044480
2010 CXCR1 blockade in breast cancer stem cells (CSCs) depletes the CSC population and induces massive apoptosis in the bulk tumor via FASL/FAS signaling; these effects are mediated by the FAK/AKT/FOXO3A pathway. CXCR1-specific blocking antibody and repertaxin (small-molecule inhibitor); in vitro CSC depletion assays; apoptosis assays; pathway inhibitor studies (FAK/AKT/FOXO3A); human breast cancer xenografts in mice The Journal of clinical investigation High 20051626
2012 DF 2156A, a dual CXCR1/CXCR2 inhibitor, acts as a non-competitive allosteric inhibitor; polar interactions stabilized by a direct ionic bond between DF 2156A and Lys99 on CXCR1 (and non-conserved Asp293 on CXCR2) are key determinants of binding; it blocks signal transduction leading to chemotaxis without altering natural ligand binding affinity. Radioligand and [³⁵S]-GTPγS binding; chemotaxis of L1.2 transfectants and human leukocytes; murine models of angiogenesis and liver ischemia/reperfusion; molecular characterization of binding mode British journal of pharmacology High 21718305
2013 Staphylococcus aureus LukED toxin targets CXCR1 and CXCR2 on neutrophils; the LukE subunit binds neutrophils in a specific and saturable manner, and this binding is inhibited by CXCL8 (the high-affinity endogenous ligand); CXCR1/2 targeting by LukED promotes killing of monocytes and neutrophils in vitro and facilitates lethality in bacteremic mice. Saturation binding assays; CXCL8 competition binding; in vitro cytotoxicity assays with CXCR1/2-expressing cells; murine systemic infection model with LukED-deficient bacteria Cell host & microbe High 24139401
2015 CXCR1-mediated neutrophil degranulation (not chemotaxis) is critical for fungal killing; Cxcr1-/- mice show decreased survival and enhanced Candida growth in the kidney due to a cell-intrinsic defect in neutrophil degranulation; the human mutant CXCR1-T276 allele also results in impaired neutrophil degranulation and fungal killing. Cxcr1-/- mouse generation; systemic candidiasis model; neutrophil trafficking and degranulation assays; human CXCR1-T276 variant functional studies; patient genetic association Science translational medicine High 26791948
2015 CXCR1 couples to G proteins through its DRY motif: D134(3.49) mutations (D134N, D134V) completely abolish ligand binding and functional response of CXCR1; point mutations M241(6.34) and F251(6.44) on TM6 generate mutant receptors with modest constitutive activity via Gα15 signaling, identifying a 'hot spot' for CXCR1 activation. Alanine/point mutagenesis of CXCR1; radioligand binding; calcium mobilization assays; G protein activation (Gα15) assays in transfected cells FEBS open bio High 25834784
2000 IL-8 stimulation of CXCR1 or CXCR2 cross-phosphorylates CCR1 and cross-desensitizes its ability to stimulate GTPase activity and Ca2+ mobilization; CCR1 cross-phosphorylates and cross-desensitizes CXCR2 but not CXCR1, revealing selective asymmetric cross-regulation among chemokine receptors. RBL-2H3 cells co-expressing CCR1 with CXCR1, CXCR2, or phosphorylation-deficient CXCR2-331T; receptor phosphorylation, GTPase stimulation, Ca2+ mobilization, and internalization assays The Journal of biological chemistry High 10734056
2001 IL-8 acutely reduces Ca2+ currents in cholinergic septal neurons expressing CXCR1 and CXCR2 mRNAs via closure of L- and N-type Ca2+ channels and activation of Giα1 and/or Giα2 G-protein subtypes; this is the first report of CXCR1 mRNA expression in the brain and of a chemokine modulating ion channels in neurons via G-proteins. Whole-cell patch clamp recording; single-cell RT-PCR from recorded neurons; pharmacological G-protein dissection Journal of neurochemistry High 11553670
2001 CXCR1 (but not CXCR2) on uroepithelial cells mediates neutrophil transepithelial migration; anti-CXCR1 antibodies inhibit IL-8-dependent neutrophil migration across infected epithelial layers by ~60%; IL-8 receptor knockout mice fail to express the receptor on mucosal cells and cannot translocate neutrophils across the epithelial barrier. Antibody blocking of CXCR1 and CXCR2 in epithelial monolayer migration assays; IL-8 receptor knockout mouse model; experimental urinary tract infection model Journal of immunology High 11046063
2016 CXCR1 and CXCR2 differentially regulate hepatocyte exosome release: CXCR1-deficient hepatocytes produce fewer exosomes and lack packaging of neutral ceramidase and sphingosine kinase enzymes required for exosome-mediated hepatocyte proliferation; CXCR2-deficient hepatocytes produce more exosomes via increased neutral sphingomyelinase activity and intracellular ceramide. CXCR1-/- and CXCR2-/- hepatocyte isolation; exosome quantification; neutral sphingomyelinase activity assays; enzyme content analysis of exosomes; hepatocyte proliferation assays PloS one Medium 27551720
2016 REEP5 and REEP6 are accessory proteins that interact specifically with CXCR1 (but not CXCR2); they facilitate ligand-stimulated endocytosis of CXCR1 and intracellular clustering of β-arrestin2 after IL-8 treatment, rather than membrane expression of CXCR1; their depletion reduces CXCR1-mediated ERK phosphorylation, actin polymerization, and cancer cell invasion. Co-immunoprecipitation (CXCR1-REEP5/6 interaction); overexpression and siRNA knockdown; receptor internalization and β-arrestin2 clustering assays; ERK phosphorylation western blot; xenograft tumor model Scientific reports Medium 27966653
2018 CXCL8-CXCR1 signaling in astrocytes activates NF-κB to upregulate IL-8 expression; in neurons, CXCR1 mediates methamphetamine-induced apoptosis via astrocyte-released IL-8; siRNA knockdown of CXCR1 in SH-SY5Y neurons reduces cleaved caspase-3 and PARP expression, and this protection is reversed by recombinant IL-8. siRNA knockdown of CXCR1 in SH-SY5Y cells; co-culture of neurons and astrocytes; western blot for apoptosis markers (caspase-3, PARP); NF-κB pathway analysis; in vivo mouse METH model Frontiers in cellular neuroscience Medium 30123110
2018 Differential CXCL8 post-translational modifications (citrullination at position 5, N-terminal truncation to CXCL8(6-77)) enhance CXCR1 internalization and Gαi-dependent signaling; all CXCL8 variants promote β-arrestin 1 and 2 recruitment to CXCR1 and CXCR2; modifications do not alter the preference (bias) between Gαi-protein and β-arrestin signaling. Chemically synthesized native and modified CXCL8 variants; internalization assays in human neutrophils; Gαi signaling assays; β-arrestin 1/2 recruitment assays International journal of molecular sciences Medium 30486423
2001 CD28 cross-linking on human neutrophils causes early upregulation of CXCR1 surface expression and concurrent increase in IL-8-induced chemotaxis, followed by receptor internalization and reduced chemotaxis at 3 hours; this demonstrates CD28-mediated regulation of CXCR1 expression and neutrophil migration. CD28 cross-linking with anti-CD28 mAb; flow cytometry for CXCR1 expression; chemotaxis assays; immunoprecipitation European journal of immunology Medium 11465111
2002 Phagocytosis down-regulates CXCR1 and CXCR2 surface expression on neutrophils via metalloproteinase-dependent proteolytic degradation (not internalization); metalloproteinase inhibitor 1,10-phenanthroline prevents this reduction; down-regulation is accompanied by reduced Ca2+ responses to corresponding ligands. Phagocytosis of opsonized yeast; flow cytometry for CXCR1/CXCR2; metalloproteinase inhibitor (1,10-phenanthroline); confocal microscopy; Ca2+ response assays Blood Medium 12239185
2001 TNF-α mediates S. aureus-induced down-regulation of CXCR1 and CXCR2 on neutrophils in whole blood; anti-TNF-α antibody abrogates this down-regulation; TNF-α-mediated decrease is associated with lower CXCR1/CXCR2 mRNA levels and is abrogated by protease inhibitors, indicating both transcriptional and proteolytic mechanisms. Whole blood stimulation with S. aureus; anti-TNF-α antibody blockade; flow cytometry; RT-PCR for mRNA; protease inhibitor experiments Clinical and experimental immunology Medium 11531949
2010 The CXCR1 N-terminal domain (34-mer peptide) interacts with phospholipid membranes (DOPC vesicles), causing motional restriction of tryptophan residues, increased fluorescence anisotropy, red edge excitation shift (REES) of 19 nm, and increased mean fluorescence lifetime; the entire N-domain interacts with the membrane in an extended fashion. Fluorescence spectroscopy (tryptophan emission, anisotropy, REES, lifetime); surface pressure measurements with DOPC vesicles Biochimica et biophysica acta Medium 20226759
2017 Human CD8+ T cells store CXCR1 in a distinct intracellular compartment (partially co-localizing with Golgi marker GM130, early endosome marker EEA1, and constitutive secretory pathway marker β2-microglobulin, but not with perforin, RANTES, or lysosomal CD63) and rapidly up-regulate it to the cell surface within minutes of activation by neutrophil supernatants (not TCR cross-linking); CXCR1 up-regulation enables functional IL-8-directed migration. Immunofluorescence microscopy with organelle markers; flow cytometry; chemotaxis assay; kinetic surface expression assay Blood Medium 16081690
2017 In zebrafish, cxcl8/cxcr1 signaling in endothelial cells positively regulates HSPC colonization of the caudal hematopoietic tissue (CHT) by increasing HSPC-endothelial cell 'cuddling', HSPC residency time, and mitotic rate; enhanced cxcr1 signaling induces an increase in CHT volume and cxcl12a expression; cxcr1 acts in a HSPC-nonautonomous manner to improve donor HSPC engraftment. Single-cell tracking (live imaging) of fluorescent HSPCs in zebrafish CHT; cxcr1 mutants; parabiotic zebrafish; pharmacological cxcr1 manipulation; measurement of HSPC-endothelial interactions The Journal of experimental medicine Medium 28351983
2023 CXCR1 drives dendritic cell-mediated inflammation via a CXCL5/CXCR1/HIF-1α positive feedback loop that directly regulates IL-6/IL-12p70 production; DC-specific CXCR1 knockout reduces inflammatory cytokine production and ameliorates EAE disease severity and LPS-induced ARDS lung injury. Global and DC-specific CXCR1 knockout mice; EAE and LPS-induced ARDS models; cytokine profiling (IL-6, IL-12p70); mechanistic pathway analysis (HIF-1α); CXCL5 antibody neutralization Cell death & disease Medium 37709757
2001 The second intracellular domain of CXCR1 has a major influence on signaling via inhibitory G proteins; replacing the second intracellular domain of CXCR1 with that of CXCR5 strongly reduces ERK1/2-MAP kinase activation and chemotaxis despite retained Gi coupling; the third and C-terminal intracellular domains of CXCR5 have only minor effects on signal transduction. Chimeric CXCR1/CXCR5 receptor constructs; pertussis toxin sensitivity assays; Ca2+ signaling; ERK1/2 MAP kinase activation; chemotaxis assays Biological chemistry Medium 11688722
2016 IL-8 promotes HNSCC cell proliferation via CXCR1/2-mediated activation of the NOD1/RIP2 signaling pathway; IL-8 siRNA knockdown reduces CXCR1/2 expression and NOD1/RIP2 signaling; NOD1 and RIP2 expression is increased by IL-8 stimulation and reduced by IL-8 siRNA, while NOD2 shows an opposite pattern. siRNA knockdown of IL-8 and CXCR1/2 in HNSCC cell lines; proliferation and clonogenicity assays; western blot and RT-PCR for NOD1, NOD2, RIP2 Oncotarget Low 27557518
2019 CXCR1 promotes gastric cancer cell proliferation, migration, and invasion through AKT and ERK1/2 phosphorylation; CXCR1 knockdown reduces cyclin D1, EGFR, VEGF, MMP-9, MMP-2, and Bcl-2 while increasing Bax and E-cadherin; CXCR1 overexpression enhances tumor growth in vivo. Stable shRNA knockdown and overexpression in gastric cancer cell lines; MTT, colony formation, flow cytometry, transwell assays; western blot for signaling molecules; xenograft mouse model International journal of oncology Low 26983663

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 635 32289253
2017 Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases. Theranostics 611 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 521 27578214
2019 CXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors. Nature communications 318 31488817
2007 Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nature medicine 263 18059279
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 235 31848188
2006 Murine CXCR1 is a functional receptor for GCP-2/CXCL6 and interleukin-8/CXCL8. The Journal of biological chemistry 175 17197447
2013 Staphylococcus aureus leukotoxin ED targets the chemokine receptors CXCR1 and CXCR2 to kill leukocytes and promote infection. Cell host & microbe 138 24139401
2000 Transepithelial neutrophil migration is CXCR1 dependent in vitro and is defective in IL-8 receptor knockout mice. Journal of immunology (Baltimore, Md. : 1950) 134 11046063
2009 Functional activity of CXCL8 receptors, CXCR1 and CXCR2, on human malignant melanoma progression. European journal of cancer (Oxford, England : 1990) 120 19683430
2003 Role of the cytoplasmic tails of CXCR1 and CXCR2 in mediating leukocyte migration, activation, and regulation. Journal of immunology (Baltimore, Md. : 1950) 120 12626541
2010 Small molecule antagonists for CXCR2 and CXCR1 inhibit human colon cancer liver metastases. Cancer letters 118 21035946
2001 The chemokine interleukin-8 acutely reduces Ca(2+) currents in identified cholinergic septal neurons expressing CXCR1 and CXCR2 receptor mRNAs. Journal of neurochemistry 116 11553670
2004 On the mechanism and significance of ligand-induced internalization of human neutrophil chemokine receptors CXCR1 and CXCR2. The Journal of biological chemistry 109 15028716
1999 beta-arrestins regulate interleukin-8-induced CXCR1 internalization. The Journal of biological chemistry 106 10347185
2007 Pharmacological characterization of Sch527123, a potent allosteric CXCR1/CXCR2 antagonist. The Journal of pharmacology and experimental therapeutics 102 17496166
2021 Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy. Molecules (Basel, Switzerland) 96 35011369
2009 CXCR1 and CXCR2 enhances human melanoma tumourigenesis, growth and invasion. British journal of cancer 95 19401689
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
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 87 36585453
1998 CXCR1 and CXCR2 are rapidly down-modulated by bacterial endotoxin through a unique agonist-independent, tyrosine kinase-dependent mechanism. Journal of immunology (Baltimore, Md. : 1950) 87 9712063
2005 2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors. Journal of medicinal chemistry 85 15974585
2013 The CXCL7/CXCR1/2 axis is a key driver in the growth of clear cell renal cell carcinoma. Cancer research 83 24335961
2021 Reduction of NETosis by targeting CXCR1/2 reduces thrombosis, lung injury, and mortality in experimental human and murine sepsis. British journal of anaesthesia 82 34893315
2018 IL-8/CXCR1/2 signalling promotes tumor cell proliferation, invasion and vascular mimicry in glioblastoma. Journal of biomedical science 82 30086759
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 76 25315007
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) 71 15294933
2012 Neutrophils recruited by CXCR1/2 signalling mediate post-incisional pain. European journal of pain (London, England) 70 23132735
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 69 32188703
2012 Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor. British journal of pharmacology 64 21718305
2004 Dimer dissociation is essential for interleukin-8 (IL-8) binding to CXCR1 receptor. The Journal of biological chemistry 64 15252057
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
2000 Regulation of the human chemokine receptor CCR1. Cross-regulation by CXCR1 and CXCR2. The Journal of biological chemistry 55 10734056
2005 A homolog of the human chemokine receptor CXCR1 is expressed in the mouse. Molecular immunology 54 16084593
2016 IL-8 promotes HNSCC progression on CXCR1/2-meidated NOD1/RIP2 signaling pathway. Oncotarget 53 27557518
2005 Cloning and characterization of mouse homolog of the CXC chemokine receptor CXCR1. Cytokine 53 15967374
2018 Cxcr1 mediates recruitment of neutrophils and supports proliferation of tumor-initiating astrocytes in vivo. Scientific reports 52 30185911
2015 CXCR1/2 antagonism with CXCL8/Interleukin-8 analogue CXCL8(3-72)K11R/G31P restricts lung cancer growth by inhibiting tumor cell proliferation and suppressing angiogenesis. Oncotarget 52 26087179
2005 CXCL8 modulates human intestinal epithelial cells through a CXCR1 dependent pathway. Cytokine 51 15579377
2010 Targeting CXCR1/CXCR2 receptor antagonism in malignant melanoma. Expert opinion on therapeutic targets 49 20230195
2022 Targeting CXCR1 and CXCR2 receptors in cardiovascular diseases. Pharmacology & therapeutics 47 35908611
2021 The IL-8-CXCR1/2 axis contributes to diabetic kidney disease. Metabolism: clinical and experimental 45 34097917
2010 CXCR1 and SLC11A1 polymorphisms affect susceptibility to cutaneous leishmaniasis in Brazil: a case-control and family-based study. BMC medical genetics 44 20089160
2023 Therapeutic inhibition of CXCR1/2: where do we stand? Internal and emergency medicine 43 37249756
2022 Ladarixin, an inhibitor of the interleukin-8 receptors CXCR1 and CXCR2, in new-onset type 1 diabetes: A multicentre, randomized, double-blind, placebo-controlled trial. Diabetes, obesity & metabolism 43 35589610
2009 Dynamic regulation of CXCR1 and CXCR2 homo- and heterodimers. Journal of immunology (Baltimore, Md. : 1950) 43 19890050
2021 An updated review on the role of the CXCL8-CXCR1/2 axis in the progression and metastasis of breast cancer. Molecular biology reports 42 34426905
2017 CXCR1 remodels the vascular niche to promote hematopoietic stem and progenitor cell engraftment. The Journal of experimental medicine 42 28351983
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
2006 Expression of the chemokine receptor CXCR1 in human glomerular diseases. Kidney international 37 16541017
2002 Phagocytosing neutrophils down-regulate the expression of chemokine receptors CXCR1 and CXCR2. Blood 37 12239185
2001 Down-regulation of CXCR1 and CXCR2 expression on human neutrophils upon activation of whole blood by S. aureus is mediated by TNF-alpha. Clinical and experimental immunology 37 11531949
2019 Interleukin-8 promotes cell migration via CXCR1 and CXCR2 in liver cancer. Oncology letters 36 31516616
2020 Structural Insights Into How Proteoglycans Determine Chemokine-CXCR1/CXCR2 Interactions: Progress and Challenges. Frontiers in immunology 35 32391006
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 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
2019 Disrupting Inflammation-Associated CXCL8-CXCR1 Signaling Inhibits Tumorigenicity Initiated by Sporadic- and Colitis-Colon Cancer Stem Cells. Neoplasia (New York, N.Y.) 33 30738331
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
2005 Expression of interleukin-8 receptors (CXCR1 and CXCR2) in premenopausal women with recurrent urinary tract infections. Clinical and diagnostic laboratory immunology 32 16339057
2001 Immunobiology of CD28 expression on human neutrophils. I. CD28 regulates neutrophil migration by modulating CXCR-1 expression. European journal of immunology 32 11465111
2020 KLF2 regulates neutrophil migration by modulating CXCR1 and CXCR2 in asthma. Biochimica et biophysica acta. Molecular basis of disease 31 32800946
2011 Optimization of purification and refolding of the human chemokine receptor CXCR1 improves the stability of proteoliposomes for structure determination. Biochimica et biophysica acta 31 22024025
2016 Chemokine Receptors, CXCR1 and CXCR2, Differentially Regulate Exosome Release in Hepatocytes. PloS one 29 27551720
2001 Signal transduction by the chemokine receptor CXCR5: structural requirements for G protein activation analyzed by chimeric CXCR1/CXCR5 molecules. Biological chemistry 28 11688722
2016 The accessory proteins REEP5 and REEP6 refine CXCR1-mediated cellular responses and lung cancer progression. Scientific reports 26 27966653
2015 The CXCR1/2 Pathway: Involvement in Diabetes Pathophysiology and Potential Target for T1D Interventions. Current diabetes reports 26 26275440
2023 Small molecule antagonist of CXCR2 and CXCR1 inhibits tumor growth, angiogenesis, and metastasis in pancreatic cancer. Cancer letters 25 37062329
2018 Role of CXCR1 and Interleukin-8 in Methamphetamine-Induced Neuronal Apoptosis. Frontiers in cellular neuroscience 25 30123110
2010 Inhibition of CXCR1 and CXCR2 chemokine receptors attenuates acute inflammation, preserves gray matter and diminishes autonomic dysreflexia after spinal cord injury. Spinal cord 25 20877331
2004 Downregulation of CXCR1 and CXCR2 expression on human neutrophils by Helicobacter pylori: a new pathomechanism in H. pylori infection? Infection and immunity 25 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 24 37760523
2012 Genetic variations of interleukin-8, CXCR1 and CXCR2 genes and risk of acute pyelonephritis in children. International journal of immunogenetics 23 22325052
2021 Conformational plasticity and dynamic interactions of the N-terminal domain of the chemokine receptor CXCR1. PLoS computational biology 22 34014914
2005 Human CD8+ T cells store CXCR1 in a distinct intracellular compartment and up-regulate it rapidly to the cell surface upon activation. Blood 21 16081690
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-126, IL-7, CXCR1/2 receptors, inflammation and circulating endothelial progenitor cells: The study on targets for treatment pathways in a model of subclinical cardiovascular disease (type 1 diabetes mellitus). Journal of translational medicine 20 33858417
2019 The antagonist of CXCR1 and CXCR2 protects db/db mice from metabolic diseases through modulating inflammation. American journal of physiology. Endocrinology and metabolism 20 31573846
2020 MMP9, CXCR1, TLR6, and MPO participant in the progression of coronary artery disease. Journal of cellular physiology 19 32052443
2016 CXCR1 promotes malignant behavior of gastric cancer cells in vitro and in vivo in AKT and ERK1/2 phosphorylation. International journal of oncology 19 26983663
2010 Membrane interaction of the N-terminal domain of chemokine receptor CXCR1. Biochimica et biophysica acta 19 20226759
2007 A haplotype of the human CXCR1 gene protective against rapid disease progression in HIV-1+ patients. Proceedings of the National Academy of Sciences of the United States of America 19 17360650
2000 Downregulation of CXCR-2 but not CXCR-1 expression by human keratinocytes by UVB. Journal of cellular physiology 19 10653603
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
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 18 34120407
2015 Characterization of G protein coupling mediated by the conserved D134(3.49) of DRY motif, M241(6.34), and F251(6.44) residues on human CXCR1. FEBS open bio 18 25834784
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
2018 Differential Effects of Posttranslational Modifications of CXCL8/Interleukin-8 on CXCR1 and CXCR2 Internalization and Signaling Properties. International journal of molecular sciences 17 30486423
2017 Differences in Sulfotyrosine Binding amongst CXCR1 and CXCR2 Chemokine Ligands. International journal of molecular sciences 17 28869519
2007 3,4-Diamino-2,5-thiadiazole-1-oxides as potent CXCR2/CXCR1 antagonists. Bioorganic & medicinal chemistry letters 17 18006311
2006 IFN gamma and CXCR-1 gene polymorphisms in idiopathic bronchiectasis. Tissue antigens 17 17026468