Affinage

CXCR2

C-X-C chemokine receptor type 2 · UniProt P25025

Length
360 aa
Mass
40.8 kDa
Annotated
2026-06-09
100 papers in source corpus 34 papers cited in narrative 34 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

CXCR2 is a G protein-coupled chemokine receptor for ELR+ CXC chemokines (CXCL1/2/5 and CXCL8/IL-8) that drives directed cell migration, most prominently neutrophil recruitment to sites of inflammation (PMID:12464676, PMID:16964312). It functions as a constitutive, ligand-independent homodimer, with the region between Ala-106 and Lys-163 required for dimerization and for productive signaling and chemotaxis (PMID:12888558), and it additionally forms constitutive heterodimers with the atypical receptor CCRL2 that regulate its surface expression and enable β2-integrin activation (PMID:28743719). Ligand discrimination is encoded at the protein level: the CXCL8 monomer is more active than the dimer for Ca2+ mobilization, phosphoinositide hydrolysis, chemotaxis and exocytosis, and CXCR2 produces more sustained ERK phosphorylation than CXCR1 (PMID:19667085), while CXCL2 variants are more potent than CXCL1 for G-protein and β-arrestin activation (PMID:32881070). Downstream, CXCR2 signals through PI3K/Akt (with Cbl phosphorylation required for chemotaxis) and through ERK1/2 and p38 MAPK (PMID:16798838, PMID:36311783), and assembles an intracellular 'chemosynapse' in which LASP-1 binds the LKIL motif (Ile323-Leu324) of the receptor C-terminal domain and IQGAP1 (residues 1-160) engages the same CTD to couple the receptor to Cdc42, focal adhesion turnover and leading-edge polarization (PMID:20419088, PMID:21876773). Receptor output is negatively regulated by β-arrestin-2, which promotes internalization and dampens Ca2+, superoxide and GTPase responses (PMID:16210646), and CXCR2 is irreversibly removed from the surface by ADAM17-mediated, ligand-independent shedding upon non-chemokine neutrophil activation (PMID:25412626). Its expression is transcriptionally controlled by PPARγ via a promoter PPRE (PMID:18292390), by NF-κB-driven chemokine circuits (PMID:16964312), and by H3K9 acetylation at its promoter (PMID:28845733). Through these mechanisms CXCR2 governs neutrophil and MDSC trafficking and immunosuppression in tumors (PMID:24848257, PMID:27265504), reinforces p53-dependent oncogene-induced senescence via an autocrine NF-κB/C/EBPβ chemokine loop (PMID:18555777), and sustains a KRAS-CXCR2 feed-forward loop in pancreatic cancer (PMID:26771140).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 High

    Established the receptor's quaternary structure: it answered whether CXCR2 acts as a monomer or oligomer by showing it forms ligand-independent constitutive homodimers required for signaling.

    Evidence Co-IP of differentially tagged CXCR2 plus truncation mutagenesis mapping a Ala-106 to Lys-163 dimerization region, with Ca2+ and chemotaxis readouts in HEK293 cells and neurons

    PMID:12888558

    Open questions at the time
    • No atomic-resolution structure of the dimer interface
    • Whether dimerization state is dynamically regulated by ligand or expression level not addressed
  2. 2005 High

    Placed β-arrestin-2 as the in vivo brake on CXCR2, resolving how the receptor is desensitized and internalized during neutrophil responses.

    Evidence β-arrestin-2 knockout mice with Ca2+, superoxide, GTPase, internalization assays and in vivo neutrophil recruitment/wound healing

    PMID:16210646

    Open questions at the time
    • Phosphorylation sites recruiting β-arrestin-2 not mapped here
    • Distinction between arrestin scaffolding vs desensitization roles unresolved
  3. 2008 High

    Defined an upstream transcriptional input by showing PPARγ directly activates CXCR2 expression, linking nuclear receptor signaling to chemokine responsiveness.

    Evidence EMSA/ChIP of a PPRE in the CXCR2 promoter, promoter assays and superoxide readout in primary human macrophages

    PMID:18292390

    Open questions at the time
    • Cooperating transcription factors at the promoter not defined
    • Physiological context driving PPARγ-dependent induction unclear
  4. 2008 High

    Connected CXCR2 to cell-autonomous senescence, showing it is both necessary and sufficient to reinforce oncogene-induced senescence through a p53-dependent autocrine chemokine network.

    Evidence shRNA screen and ectopic overexpression in primary human fibroblasts with p53 and NF-κB/C/EBPβ pathway analysis

    PMID:18555777

    Open questions at the time
    • Direct receptor-to-p53 signaling intermediates not mapped
    • Whether autocrine chemokine identity determines senescence strength untested
  5. 2009 High

    Showed that ligand oligomeric state encodes signaling bias, distinguishing CXCR2 from CXCR1 in regulation and ERK kinetics.

    Evidence Trapped CXCL8 monomer (L25NMe) and dimer (R26C) variants on neutrophils and RBL-2H3 cells expressing CXCR1 or CXCR2, multiple functional and regulatory assays

    PMID:19667085

    Open questions at the time
    • Structural basis for differential CXCR1/CXCR2 regulation not resolved
    • In vivo relevance of monomer/dimer bias not addressed
  6. 2010 High

    Identified the molecular scaffold of directed migration by mapping a direct LASP-1 interaction to the CXCR2 C-terminal LKIL motif controlling chemotaxis and focal adhesion turnover.

    Evidence Proteomic co-IP, direct binding with residue-level mutagenesis (Ile323-Leu324), co-localization and FAK pathway analysis in dHL-60 neutrophil-like cells

    PMID:20419088

    Open questions at the time
    • Stoichiometry of the chemosynapse not defined
    • Whether LASP-1 binding is regulated by receptor phosphorylation unknown
  7. 2011 Medium

    Extended the chemosynapse model by adding IQGAP1 as a direct CTD partner linking the receptor to Cdc42 at the leading edge.

    Evidence Proteomic co-IP, domain mapping (IQGAP1 aa 1-160), co-localization and CXCL8-stimulated Cdc42 association in human neutrophils

    PMID:21876773

    Open questions at the time
    • Single-lab finding without reciprocal validation in other systems
    • Order of LASP-1 vs IQGAP1 assembly on the CTD unclear
  8. 2014 High

    Defined an irreversible, ligand-independent off-switch by identifying ADAM17 as the protease that sheds CXCR2 upon non-chemokine neutrophil activation.

    Evidence ADAM17 inhibitor, blocking antibody and gene-targeted mice with surface expression and in vivo acute inflammation readouts

    PMID:25412626

    Open questions at the time
    • Cleavage site on CXCR2 not mapped
    • Signals triggering ADAM17 activation toward CXCR2 not defined
  9. 2016 High

    Demonstrated cell-autonomous CXCR2 requirement in myeloid MDSCs for tumor trafficking and immunosuppression that limits checkpoint blockade.

    Evidence CXCR2-deficient mice, anti-CXCR2 antibody, bone marrow reconstitution and anti-PD1 combination in rhabdomyosarcoma

    PMID:24848257

    Open questions at the time
    • Chemokine ligands recruiting MDSCs not specified here
    • Whether MDSC CXCR2 signaling differs mechanistically from neutrophil signaling unaddressed
  10. 2017 High

    Identified CCRL2 heterodimerization as a regulator of CXCR2 surface expression and β2-integrin activation, broadening the receptor's interaction repertoire.

    Evidence Co-IP, CCRL2 knockout mice, in vitro β2-integrin activation and inflammatory arthritis models

    PMID:28743719

    Open questions at the time
    • Heterodimer interface not mapped
    • Mechanism by which CCRL2 alters CXCR2 signaling bias unresolved
  11. 2017 High

    Linked CXCR2 to innate inflammasome output by placing PKCμ-ILK between the receptor and NLRP3 activation in macrophages.

    Evidence siRNA and pharmacologic inhibition of CXCR2/ILK/PKCμ with inflammasome assays and in vivo carrageenan and M. tuberculosis models

    PMID:28739876

    Open questions at the time
    • Direct biochemical link from receptor to PKCμ not established
    • G protein coupling to this pathway not defined
  12. 2016 Medium

    Revealed a KRAS-CXCR2 feed-forward loop in pancreatic ductal cells where receptor inhibition lowers KRAS protein, defining an oncogenic autocrine circuit.

    Evidence CXCR2 knockdown and antagonists in KRAS(G12D) pancreatic duct cells, KRAS Western blot and Pdx1-cre;LSL-Kras(G12D) mice

    PMID:26771140

    Open questions at the time
    • Mechanism by which CXCR2 stabilizes KRAS protein unknown
    • Single-lab finding without orthogonal confirmation
  13. 2019 High

    Provided structural insight into ligand regulation by GAGs, showing chemokine heterodimer formation and heparin binding modulate CXCR2 receptor engagement.

    Evidence Solution NMR and MD with disulfide-trapped CXCL7-CXCL1 heterodimer and Ca2+ release assays; separately, Evasin-3 NMR mapping of the CXCL8 GAG/CXCR2-binding site with neutrophil migration assays

    PMID:28368308 PMID:31235521

    Open questions at the time
    • No co-structure of chemokine bound to CXCR2 itself
    • In vivo significance of heterodimer-GAG competition not tested
  14. 2019 High

    Placed CXCR2 in hematopoietic stem cell regulation, showing extracellular DEK acts through CXCR2 and HSPGs to control HSC self-renewal via ERK/AKT/p38.

    Evidence Cxcr2-/- mice, blocking antibodies, HSPG inhibitors, transplantation, colony and phosphorylation assays with DEK mutants

    PMID:31107242

    Open questions at the time
    • Whether DEK is a direct CXCR2 agonist not biochemically established
    • Relative contribution of HSPG vs CXCR2 binding not separated
  15. 2023 High

    Established CXCR2 as a disease driver in myelofibrosis, where CXCL8/CXCR2 promotes malignant HSPC fitness and fibrosis and synergizes with JAK inhibition.

    Evidence Single-cell transcriptomics, primary MF patient cells, hMPLW515L murine model with Cxcr2 deletion, CXCR1/2 and JAK inhibitor combination

    PMID:36800567

    Open questions at the time
    • Cell-of-origin for pathogenic CXCR2 signaling not fully resolved
    • Direct downstream effectors of fibrosis induction not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct CXCR2 signaling outputs (G-protein vs β-arrestin, homodimer vs CCRL2 heterodimer, monomer vs dimer ligand) are integrated to specify divergent cellular outcomes — chemotaxis, senescence, inflammasome activation, KRAS stabilization — remains unresolved.
  • No unified structural model of CXCR2 in its dimeric/heterodimeric states
  • Biased agonism rules across ligands not systematically defined
  • Mechanistic links from receptor to non-canonical outputs (KRAS protein levels, p53) not biochemically traced

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 2 GO:0001618 virus receptor activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-8953897 Cellular responses to stimuli 1
Partners
ADAM17ARRB2CCRL2CDC42CXCL1CXCL8IQGAP1LASP1
Complex memberships
CXCR2 chemosynapse (with LASP-1 and IQGAP1)CXCR2 homodimerCXCR2-CCRL2 heterodimer

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 CXCR2 knockdown alleviates both replicative and oncogene-induced senescence (OIS) in primary human fibroblasts, while ectopic CXCR2 expression induces premature senescence via a p53-dependent mechanism. Cells undergoing OIS secrete multiple CXCR2-binding chemokines (e.g., IL-8, GROα) regulated by NF-κB and C/EBPβ transcription factors, and coordinately upregulate CXCR2, establishing an autocrine/paracrine senescence-reinforcing secretory network. shRNA screen in primary human fibroblasts, ectopic overexpression, p53 pathway analysis, NF-κB/C/EBPβ transcription factor analysis Cell High 18555777
2003 CXCR2 forms constitutive homodimers in a ligand-independent manner; the region between amino acids Ala-106 and Lys-163 is required for homodimerization. Truncated CXCR2 mutants that disrupt homodimerization impair receptor signaling and chemotaxis, establishing that CXCR2 functions as a dimer. CXCR1 does not dimerize with CXCR2. Co-immunoprecipitation of GFP- and V5-tagged CXCR2, truncation/deletion mutagenesis, functional assays (calcium signaling, chemotaxis) in HEK293 cells and cerebellar neurons The Journal of biological chemistry High 12888558
2005 β-arrestin-2 is a negative regulator of CXCR2 signaling in vivo. Deletion of β-arrestin-2 in mice increases CXCR2-mediated Ca2+ mobilization, superoxide anion production, and GTPase activity in neutrophils, while decreasing receptor internalization. β-arrestin-2 deficiency also enhances neutrophil recruitment to CXCL1 in vivo and accelerates wound re-epithelialization. β-arrestin-2 knockout mouse model, Ca2+ mobilization assay, receptor internalization assay, GTPase assay, superoxide production assay, dorsal air pouch model, excisional wound healing model Journal of immunology High 16210646
2009 CXCL8 monomer is more active than dimer for intracellular Ca2+ mobilization, phosphoinositide hydrolysis, chemotaxis, and exocytosis via both CXCR1 and CXCR2. Receptor regulation differs: CXCR1 is more rapidly regulated (phosphorylation, desensitization, β-arrestin translocation, internalization) by the monomer, whereas CXCR2 responds similarly to both monomer and dimer for these regulatory activities. ERK phosphorylation is more sustained through CXCR2 than CXCR1. Trapped non-associating CXCL8 monomer (L25NMe) and non-dissociating dimer (R26C) tested on human neutrophils and RBL-2H3 cells stably expressing CXCR1 or CXCR2; Ca2+ mobilization, phosphoinositide hydrolysis, chemotaxis, exocytosis, receptor phosphorylation, desensitization, β-arrestin translocation, internalization, ERK phosphorylation assays Journal of immunology High 19667085
2010 LASP-1 (LIM and SH3 protein-1) is a novel binding partner of CXCR2 that co-immunoprecipitates and co-localizes with CXCR2 at the leading edge of migrating cells. The LIM domain of LASP-1 directly binds the carboxy-terminal domain (CTD) of CXCR2, with Ile323-Leu324 of the conserved LKIL motif on CXCR2-CTD identified as the binding site. Disruption of this interaction inhibits CXCR2-mediated chemotaxis and focal adhesion turnover involving Src, paxillin, PAK1, p130CAS and ERK1/2. Proteomic co-immunoprecipitation from neutrophil-like dHL-60 cells, co-localization by microscopy, direct binding assay, site-directed and deletion mutagenesis, dominant negative and knockdown approaches, chemotaxis assays, focal adhesion kinase pathway analysis PloS one High 20419088
2011 IQGAP1 is a novel CXCR2-interacting protein identified by proteomics; amino acids 1-160 of IQGAP1 directly interact with the carboxyl-terminal domain of CXCR2. CXCR2 co-localizes with IQGAP1 at the leading edge of polarized neutrophils, and CXCL8 stimulation enhances IQGAP1 association with Cdc42, placing IQGAP1 as an essential component of the CXCR2 'chemosynapse'. Proteomics co-immunoprecipitation, direct binding assay (domain mapping), co-localization by immunofluorescence in human neutrophils and dHL-60 cells, CXCL8-stimulated signaling assays PloS one Medium 21876773
2014 ADAM17 (TACE) mediates ligand-independent, irreversible CXCR2 shedding/down-regulation from the surface of mouse and human neutrophils upon overt neutrophil activation by non-ligand stimuli, but not upon chemokine ligand binding. Blocking ADAM17 reduces CXCR2 down-regulation on circulating neutrophils and enhances neutrophil recruitment during acute inflammation in vivo. Selective ADAM17 inhibitor, ADAM17 function-blocking antibody, ADAM17 gene-targeted mice, CXCR2 surface expression assay, in vivo acute inflammation model with CXCR2 inhibitor reversal Journal of leukocyte biology High 25412626
2017 CCRL2, an atypical chemokine receptor, constitutively forms heterodimers with CXCR2 on neutrophils. CCRL2 heterodimerization regulates CXCR2 membrane expression and promotes CXCR2 functions including activation of β2-integrins. CCRL2-deficient mice show defective neutrophil recruitment and are protected in two models of inflammatory arthritis. Co-immunoprecipitation (heterodimer detection), CCRL2 knockout mouse model, in vitro β2-integrin activation assay, in vivo inflammatory arthritis models Blood High 28743719
2017 CXCR2-driven activation of NLRP3 inflammasome in macrophages proceeds via a protein kinase Cμ-dependent integrin-linked kinase (ILK) pathway. CXCL1 and CXCL2 signaling through CXCR2 enhances NLRP3 inflammasome activation and subsequent bioactive IL-1β production; blocking ILK or PKCμ by siRNA or pharmacological inhibitors compromises inflammasome activation. siRNA knockdown of CXCR2, ILK, PKCμ; pharmacological inhibitors; NLRP3 inflammasome activation assays; in vivo mouse models of carrageenan-induced inflammation; in vivo M. tuberculosis infection model Journal of immunology High 28739876
2008 PPARγ transcriptionally activates CXCR2 expression in human macrophages by binding a PPAR response element (PPRE) in the CXCR2 promoter, increasing CXCR2 mRNA and membrane protein. PPARγ ligand-induced CXCR2 upregulation confers responsiveness to CXCR2 ligands (IL-8, GROβ) as measured by superoxide anion production. EMSA, ChIP, transient transfection/promoter assays, PPARγ ligand treatment of primary human macrophages; flow cytometry for membrane protein; superoxide production assay Arteriosclerosis, thrombosis, and vascular biology High 18292390
2006 PKCα activation in keratinocytes drives CXCR2-dependent neutrophil infiltration into the epidermis through NF-κB-dependent production of KC (CXCL1) and MIP-2 (CXCL2). Genetic ablation of CXCR2 in transgenic PKCα-overexpressing mice, or neutralizing antibodies against KC or MIP-2, prevents neutrophil infiltration. Systemic neutrophilia is mediated by G-CSF independently of CXCR2. Transgenic mouse model (K5-PKCα), CXCR2 knockout, neutralizing antibodies against KC/MIP-2, NF-κB pathway analysis, in vitro keratinocyte culture The Journal of clinical investigation High 16964312
2006 CXCR2 is constitutively expressed on oligodendrocytes in the CNS, while its ligand CXCL1 is induced on astrocytes by IL-1β. In human fetal astrocyte cultures, IL-1β stimulation drives high-level CXCL1 synthesis. This CXCR2/CXCL1 signaling provides a mechanism for recruitment of oligodendrocytes to areas of demyelination in multiple sclerosis. Immunohistochemistry of MS lesions, in vitro human fetal astrocyte and oligodendrocyte cultures, IL-1β stimulation assay, protein expression analysis Glia Medium 16086366
2007 CXCR2 expressed on resident lung cells (not on migrating mast cell progenitors themselves) is required for antigen-induced mast cell progenitor (MCp) recruitment to the lung and subsequent intraepithelial mast cell levels. CXCR2 deficiency reduces VCAM-1 transcripts and endothelial surface expression, linking CXCR2 signaling to regulation of endothelial VCAM-1 that is required for MCp migration. CXCR2-deficient mice, bone marrow reconstitution experiments (reciprocal BM transfers between WT and CXCR2-/- mice), anti-α4 integrin blocking mAb, VCAM-1 mRNA and surface protein quantification Proceedings of the National Academy of Sciences High 18077323
2006 CXCR2 and its ligands KC/CXCL1 and MIP-2/CXCL2/3 mediate neutrophil sequestration and lung injury in ventilator-induced lung injury (VILI). In vivo inhibition of CXCR2/CXC chemokine ligand interactions markedly reduces neutrophil sequestration and lung injury, confirmed in CXCR2-/- mice. Murine VILI model, in vivo anti-CXCR2 antibody blockade, CXCR2-/- mice, neutrophil counts, lung injury scoring The Journal of clinical investigation High 12464676
2006 IL-8-mediated migration of liver cancer cells (Huh-7 and HepG2) occurs via both CXCR1 and CXCR2; pretreatment with anti-CXCR1 or anti-CXCR2 antibodies markedly inhibits IL-8-directed cell migration in vitro. In vitro wound healing assay, migration assay, receptor-blocking antibodies against CXCR1 and CXCR2 Oncology letters Medium 31516616
2010 CXCR2 promotes ovarian cancer cell cycle progression by modulating p21(waf1/cip1), cyclin D1, CDK6, CDK4, cyclin A, and cyclin B1; inhibits apoptosis by suppressing p-p53/Puma/Bcl-xS and activating Bcl-xL/Bcl-2; and stimulates angiogenesis by increasing VEGF and decreasing thrombospondin-1 through MAPK and NF-κB pathways. These effects were established by stable shRNA knockdown of CXCR2. Stable shRNA knockdown of CXCR2 in ovarian cancer cell lines, Western blot for cell cycle proteins and apoptosis markers, EMSA for NF-κB, ELISA for VEGF/thrombospondin-1, flow cytometry, mouse xenograft model Clinical cancer research Medium 20505188
2009 CMV-encoded vCXCL1 (UL146 gene product) acts as a highly efficacious agonist on both CXCR1 and CXCR2 with affinities of 44 nM and 5.6 nM respectively, activating calcium mobilization, phosphatidylinositol turnover, and chemotaxis. vCXCL1 does not activate or block the other 16 classified human chemokine receptors. Calcium mobilization assay, competition binding against radiolabeled CXCL8, inositol triphosphate turnover, chemotaxis assay using CXCR1- and CXCR2-expressing CHO, 300.19, COS7, and L1.2 cells; panel of 18 human chemokine receptors screened The Journal of biological chemistry High 20044480
2019 Extracellular DEK protein regulates hematopoietic stem cell (HSC) numbers and self-renewal through CXCR2 and heparan sulfate proteoglycans (HSPGs), with downstream activation of ERK1/2, AKT, and p38 MAPK. CXCR2-/- mice, CXCR2-blocking antibodies, and HSPG inhibitors all abolish DEK-mediated effects on HSC/HPC numbers. Cxcr2-/- mice, blocking CXCR2 antibodies, 3 different HSPG inhibitors, flow cytometry, transplantation assays, colony formation assays, phosphorylation assays (ERK1/2, AKT, p38 MAPK); DEK mutants lacking nuclear translocation signal or DNA-binding domain The Journal of clinical investigation High 31107242
2016 CXCR2 deficiency in the myeloid compartment (confirmed by bone marrow reconstitution) prevents CD11b+Ly6Ghi MDSC trafficking to tumor sites in rhabdomyosarcoma, establishing that CXCR2 on MDSCs mediates local immunosuppression that limits checkpoint blockade efficacy. CXCR2-deficient mice, anti-CXCR2 monoclonal antibody therapy, adoptive transfer/bone marrow reconstitution, flow cytometry for MDSC characterization, anti-PD1 combination therapy Science translational medicine High 24848257
2006 CXCL8-induced chemotaxis via CXCR2 requires PI3K/Akt signaling and Cbl phosphorylation; Cbl and Akt regulate CXCR2-mediated chemotaxis. PI3K associates with Cbl upon CXCL8 stimulation. Kinase-dead Akt mutant decreases CXCR2-mediated chemotaxis and Cbl phosphorylation. Proteasome inhibition blocks CXCL8-induced internalization of CXCR2. CXCR2-overexpressing L1.2 cells, PI3K inhibitor (LY294002), tyrosine kinase inhibitor, proteasome inhibitors, overexpression of WT and mutant Cbl/Akt constructs, co-immunoprecipitation of PI3K p85 with Cbl, chemotaxis assay, internalization assay International immunology Medium 16798838
2019 CXCL5 and CXCL8 activate CXCR2 on human brain endothelial cells (hCMEC/D3), causing Akt/PKB phosphorylation, redistribution of tight junction ZO-1, actin stress fiber formation, and decreased paracellular barrier function. CXCR2 expression is inflammation-inducible on brain endothelium, and selective CXCR2 antagonism (SB332235) partially prevents chemokine-induced tight junction disruption. Human cerebral microvascular endothelial cell line hCMEC/D3, recombinant CXCL5/CXCL8 treatment, real-time electrical impedance sensing for barrier function, immunofluorescence for ZO-1 and actin, Western blot for Akt phosphorylation, selective CXCR2 antagonist SB332235, IHC of human MS brain biopsies International journal of molecular sciences Medium 30704100
2017 CXCR2 in CXCR2(+)CD11b(+)Ly6Ghi MDSCs is required for their trafficking to pancreatic tumors; genetic ablation of CXCR2 abrogates metastasis, and combined CXCR2 inhibition with anti-PD1 significantly extends survival in established pancreatic cancer disease. Genetic ablation and pharmacologic inhibition of CXCR2 in KPC mouse model, neutrophil/MDSC depletion, flow cytometry for T cell infiltration, anti-PD1 combination therapy, survival analysis Cancer cell High 27265504
2020 Cxcl2 variants are more potent than Cxcl1 variants for Cxcr2 G-protein and β-arrestin receptor activation, while native Cxcl1 and its dimers bind heparan sulfate (HS) glycosaminoglycans with higher affinity than Cxcl2 variants. Peritoneal neutrophil recruitment cannot be solely attributed to Cxcr2 activation or GAG interactions alone, and their relationship is highly context-dependent. Cxcr2 G-protein and β-arrestin activity assays, GAG heparan sulfate binding assay, peritoneal neutrophil recruitment assay, flow cytometry for Cxcr2 and CD11b on neutrophils, engineered trapped dimer variants of Cxcl1 and Cxcl2 Journal of leukocyte biology High 32881070
2017 NMR and molecular dynamics reveal that CXCL7 forms heterodimers with CXCL1 and CXCL4 through packing interactions, while electrostatic repulsion disfavors CXCL7-CXCL8 heterodimer. A disulfide-trapped CXCL7-CXCL1 heterodimer is highly active in Ca2+ release assay via CXCR2 but GAG (heparin) binding to the heterodimer prevents receptor binding, suggesting GAG interactions regulate heterodimer function. Solution NMR spectroscopy, molecular dynamics simulation, disulfide-linked trapped heterodimer engineering, Ca2+ release assay (CXCR2 activation), heparin binding studies International journal of molecular sciences High 28368308
2019 CXCR2 on bone marrow stroma (in addition to granulocytes) is involved in HSPC localization and egress; combined targeting of CXCR2 (agonist) and VLA4 integrin achieves rapid, synergistic mobilization of HSPCs including true HSCs in mice. CXCR2 agonist administration, VLA4 inhibitor, mechanistic studies using CXCR2 expressed on BM stroma vs granulocytes, HSPC flow cytometry, in vivo mobilization assays in mice The Journal of clinical investigation Medium 31085833
2019 CXCR2 supports nociceptive sensitization after traumatic brain injury (TBI) through an epigenetic mechanism: TBI enhances association of the CXCR2 promoter with acetylated-H3K9 histone (assessed by ChIP), leading to spinal cord CXCR2 upregulation in neurons. Systemic or intrathecal CXCR2 antagonist (SCH527123) reverses hindpaw allodynia after TBI. Rat lateral fluid percussion TBI model, chromatin immunoprecipitation (ChIP) for H3K9 acetylation at CXCR2 promoter, CXCR2 antagonist (SCH527123) systemic and intrathecal administration, immunohistochemistry, Western blot, ELISA for CXCL1 Molecular pain Medium 28845733
2019 CXCL1/CXCR2 signaling in the hippocampus contributes to chronic stress-induced depression in mice; CXCR2 inhibition (SB265610) prevents chronic stress-induced depression-like behaviors, inhibits GSK3β activity, blocks apoptosis pathways (reduced caspase-3, Bax), and restores BDNF and CREB expression. Intrahippocampal CXCL1 overexpression activates GSK3β and suppresses CREB/BDNF. Unpredictable chronic mild stress (UCMS) mouse model, intrahippocampal microinjection of lenti-CXCL1, CXCR2 inhibitor SB265610, GSK3β inhibitor AR-A014418, Western blot for caspase-3/Bax/CREB/BDNF, behavioral assays FASEB journal Medium 31034777
2019 NMR structural analysis shows that tick salivary protein Evasin-3 disrupts the glycosaminoglycan-binding site of CXCL8 and inhibits CXCL8 interaction with CXCR2. Synthetic Evasin-3 variants effectively inhibit CXCL8-induced migration of polymorphonuclear neutrophils. Solution NMR spectroscopy of Evasin-3/CXCL8 complex, surface plasmon resonance for binding affinity, neutrophil migration assay The Journal of biological chemistry High 31235521
2023 CXCL8/CXCR2 signaling drives bone marrow fibrosis in myelofibrosis; CXCL8 promotes proliferation and fitness of MF hematopoietic stem/progenitor cells in vitro. Genetic deletion of Cxcr2 in a murine MF model abrogates fibrosis and extends overall survival; pharmacologic CXCR1/2 pathway inhibition improves hematologic parameters, attenuates fibrosis, and synergizes with JAK inhibitor therapy. Single-cell transcriptomics, cytokine secretion studies in primary MF patient cells, hMPLW515L murine adoptive transfer model with Cxcr2 genetic deletion, pharmacologic CXCR1/2 inhibitor, JAK inhibitor combination, in vitro proliferation with exogenous CXCL8 Blood High 36800567
2016 CXCR2 signaling in KRASG12D-bearing pancreatic ductal cells mediates autocrine tumor cell proliferation; knockdown or pharmacological inhibition of CXCR2 reduces in vitro and in vivo tumor cell proliferation. Importantly, both genetic and pharmacological CXCR2 inhibition reduces KRAS protein levels, revealing a KRAS-CXCR2 feed-forward loop. CXCR2 knockdown in human KRAS(G12D)-bearing pancreatic duct-derived cells, CXCR2 antagonists (pharmacologic), in vitro proliferation assays, in vivo tumor growth, KRAS protein quantification by Western blot, Pdx1-cre;LSL-Kras(G12D) mouse model Oncotarget Medium 26771140
2022 CXCR2 deficiency in Cxcr2 knockout mice decreases the percentage of mature neutrophils in spleen, increases aged CD62Llo CXCR4hi neutrophils in spleen, reduces phagocytic ability and reactive oxygen species production of spleen neutrophils, reduces F-actin and α-tubulin levels, and impairs ERK1/2, p38 MAPK, PI3K-AKT, NF-κB, TGFβ and IFNγ signaling pathways in neutrophils. Cxcr2 knockout mice, flow cytometry, phagocytosis assay, ROS production assay, F-actin/α-tubulin quantification, Western blot for signaling pathways Frontiers in immunology Medium 36311783
2021 CXCL2-CXCR2 signaling mediates colon cancer cell adhesion to extracellular matrix proteins (vitronectin, fibronectin, fibrinogen) in a CXCR2-dependent manner, and this adhesion requires αV integrin. In vivo, CXCR2 antagonism reduces peritoneal metastatic nodules by 70%, and αV integrin immunoneutralization reduces nodules by 69%, placing CXCL2-CXCR2 upstream of αV integrin in peritoneal metastasis. CXCR2 antagonist SB225002, αV integrin-blocking antibody, in vitro ECM adhesion assay, in vivo peritoneal metastasis mouse model (laparotomy + CT-26 cells), gene expression analysis of CXCL2 Clinical & experimental metastasis Medium 34115261
2020 CXCL5-CXCR2 signaling constitutes a senescence-associated secretory phenotype (SASP) in aging mouse and human embryos; CXCL5 treatment of young mouse embryos decreases implantation rates and increases expression of aging markers (P53, P21, PAI-1, IL-6). Suppression of CXCL5-CXCR2 signaling in aging mouse embryos by neutralizing antibodies or receptor antagonist improves implantation rate and pregnancy outcomes. Microarray analysis of aging human blastocysts, mouse embryo culture with recombinant CXCL5, CXCR2 antagonist, CXCL5 neutralizing antibody, implantation assays, pregnancy and delivery outcomes, gene expression analysis Aging cell Medium 32959976
2017 CXCR2 promotes breast cancer metastasis and chemoresistance via suppression of AKT1 and activation of COX2 (PTGS2). Mechanistically, CXCR2 promotes EMT, anti-apoptosis, and anti-senescence of breast cancer cells, with AKT1 and COX2 acting as downstream mediators inversely controlling these phenotypes. CXCR2 overexpression/knockdown in breast cancer cell lines, Western blot for AKT1, COX2, EMT markers, apoptosis markers, senescence assays, correlation with clinical tissue data Cancer letters Low 28964785

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 1448 18555777
2016 CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma. Cancer cell 742 27265504
2020 CXCR1 and CXCR2 Chemokine Receptor Agonists Produced by Tumors Induce Neutrophil Extracellular Traps that Interfere with Immune Cytotoxicity. Immunity 655 32289253
2014 Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Science translational medicine 649 24848257
2002 Critical role for CXCR2 and CXCR2 ligands during the pathogenesis of ventilator-induced lung injury. The Journal of clinical investigation 387 12464676
2009 Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 372 19904283
2012 Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis. The Journal of clinical investigation 330 22922255
2022 METTL3 Inhibits Antitumor Immunity by Targeting m6A-BHLHE41-CXCL1/CXCR2 Axis to Promote Colorectal Cancer. Gastroenterology 211 35700773
2008 CXCR2 antagonists for the treatment of pulmonary disease. Pharmacology & therapeutics 186 19026683
2021 Targeting CXCR2 inhibits the progression of lung cancer and promotes therapeutic effect of cisplatin. Molecular cancer 178 33814009
1999 Expression and function of the chemokine receptors CXCR1 and CXCR2 in sepsis. Journal of immunology (Baltimore, Md. : 1950) 174 9973513
2022 CXCR2 inhibition enables NASH-HCC immunotherapy. Gut 169 35477863
2012 CXCR2: From Bench to Bedside. Frontiers in immunology 160 22936934
2009 Differential activation and regulation of CXCR1 and CXCR2 by CXCL8 monomer and dimer. Journal of immunology (Baltimore, Md. : 1950) 159 19667085
2015 IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells. Blood 158 25810490
2010 CXCR2 promotes ovarian cancer growth through dysregulated cell cycle, diminished apoptosis, and enhanced angiogenesis. Clinical cancer research : an official journal of the American Association for Cancer Research 155 20505188
2017 CXCL1/CXCR2 signaling in pathological pain: Role in peripheral and central sensitization. Neurobiology of disease 130 28587921
2017 CXCL1 and CXCL2 Regulate NLRP3 Inflammasome Activation via G-Protein-Coupled Receptor CXCR2. Journal of immunology (Baltimore, Md. : 1950) 129 28739876
2022 CXCR2 Receptor: Regulation of Expression, Signal Transduction, and Involvement in Cancer. International journal of molecular sciences 121 35216283
2020 Neutrophil recruitment by chemokines Cxcl1/KC and Cxcl2/MIP2: Role of Cxcr2 activation and glycosaminoglycan interactions. Journal of leukocyte biology 119 32881070
2000 Interleukin-8 and its receptor CXCR2 in atherosclerosis. Immunologic research 116 10852110
2011 Overexpression of CXCL1 and its receptor CXCR2 promote tumor invasion in gastric cancer. Annals of oncology : official journal of the European Society for Medical Oncology 112 21343381
2006 Blockade of the chemokine receptor CXCR2 inhibits pancreatic cancer cell-induced angiogenesis. Cancer letters 111 16458421
2006 Role for CXCR2 and CXCL1 on glia in multiple sclerosis. Glia 110 16086366
2016 Genetic and Pharmacologic Inhibition of the Chemokine Receptor CXCR2 Prevents Experimental Hypertension and Vascular Dysfunction. Circulation 105 27678262
2009 CXCR1 and CXCR2 enhances human melanoma tumourigenesis, growth and invasion. British journal of cancer 95 19401689
2017 CXCR2 promotes breast cancer metastasis and chemoresistance via suppression of AKT1 and activation of COX2. Cancer letters 94 28964785
2003 Ligand-independent CXCR2 dimerization. The Journal of biological chemistry 88 12888558
2017 The atypical receptor CCRL2 is required for CXCR2-dependent neutrophil recruitment and tissue damage. Blood 87 28743719
2017 A positive crosstalk between CXCR4 and CXCR2 promotes gastric cancer metastasis. Oncogene 85 28481874
2017 CXCR2+ MDSCs promote breast cancer progression by inducing EMT and activated T cell exhaustion. Oncotarget 85 29383101
2012 CXCR2 in acute lung injury. Mediators of inflammation 83 22719179
2007 Pulmonary CXCR2 regulates VCAM-1 and antigen-induced recruitment of mast cell progenitors. Proceedings of the National Academy of Sciences of the United States of America 80 18077323
2012 Chemokine receptor CXCR2: physiology regulator and neuroinflammation controller? Journal of neuroimmunology 79 22445294
2006 Exercise induces interleukin-8 receptor (CXCR2) expression in human skeletal muscle. Experimental physiology 78 17030560
2008 Control of senescence by CXCR2 and its ligands. Cell cycle (Georgetown, Tex.) 75 18838863
2004 Variants of the IL8 and IL8RB genes and risk for gastric cardia adenocarcinoma and esophageal squamous cell carcinoma. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 75 15598788
2005 Altered CXCR2 signaling in beta-arrestin-2-deficient mouse models. Journal of immunology (Baltimore, Md. : 1950) 74 16210646
2019 Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumorigenicity in glioblastoma. Cell death & disease 70 30926789
2006 CXCR2 ligands and G-CSF mediate PKCalpha-induced intraepidermal inflammation. The Journal of clinical investigation 69 16964312
2009 A role for CXCR2 in senescence, but what about in cancer? Cancer research 65 19276354
2023 CXCR2 chemokine receptor - a master regulator in cancer and physiology. Trends in molecular medicine 63 37872025
2016 CXCR2 and CXCL4 regulate survival and self-renewal of hematopoietic stem/progenitor cells. Blood 61 27222476
2009 The cytomegalovirus UL146 gene product vCXCL1 targets both CXCR1 and CXCR2 as an agonist. The Journal of biological chemistry 60 20044480
2020 CXCR2 signaling promotes secretory cancer-associated fibroblasts in pancreatic ductal adenocarcinoma. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 59 32453916
2015 Cell growth density modulates cancer cell vascular invasion via Hippo pathway activity and CXCR2 signaling. Oncogene 58 25772246
2018 CXCR2-Expressing Tumor Cells Drive Vascular Mimicry in Antiangiogenic Therapy-Resistant Glioblastoma. Neoplasia (New York, N.Y.) 56 30236892
2010 LIM and SH3 protein-1 modulates CXCR2-mediated cell migration. PloS one 55 20419088
2015 CXCR2 inhibition suppresses acute and chronic pancreatic inflammation. The Journal of pathology 54 25950520
2008 Expression of CXCL8, CXCR1, and CXCR2 in neurons and glial cells of the human and rabbit retina. Investigative ophthalmology & visual science 51 18552386
2023 CXCL8/CXCR2 signaling mediates bone marrow fibrosis and is a therapeutic target in myelofibrosis. Blood 50 36800567
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
2013 CXCR2: a target for pancreatic cancer treatment? Expert opinion on therapeutic targets 47 23425074
2021 CXCL5/CXCR2 modulates inflammation-mediated neural repair after optic nerve injury. Experimental neurology 46 33785307
2019 The role of CXCR2 in acute inflammatory responses and its antagonists as anti-inflammatory therapeutics. Current opinion in hematology 44 30407218
2017 Preclinical chorioamnionitis dysregulates CXCL1/CXCR2 signaling throughout the placental-fetal-brain axis. Experimental neurology 44 29117499
2019 The chemokine CXCL1 and its receptor CXCR2 contribute to chronic stress-induced depression in mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 43 31034777
2024 Targeting ESE3/EHF With Nifurtimox Inhibits CXCR2+ Neutrophil Infiltration and Overcomes Pancreatic Cancer Resistance to Chemotherapy and Immunotherapy. Gastroenterology 42 38492894
2022 CXCL1-CXCR2 signalling mediates hypertensive retinopathy by inducing macrophage infiltration. Redox biology 40 35981418
2019 Targeting VLA4 integrin and CXCR2 mobilizes serially repopulating hematopoietic stem cells. The Journal of clinical investigation 40 31085833
2009 Enhanced expression and clinical significance of chemokine receptor CXCR2 in hepatocellular carcinoma. The Journal of surgical research 40 20018298
2021 CXCL2-CXCR2 axis mediates αV integrin-dependent peritoneal metastasis of colon cancer cells. Clinical & experimental metastasis 39 34115261
2020 The CXCR2/CXCL2 signalling pathway - An alternative therapeutic approach in high-grade glioma. European journal of cancer (Oxford, England : 1990) 37 31927212
2020 Structural Insights Into How Proteoglycans Determine Chemokine-CXCR1/CXCR2 Interactions: Progress and Challenges. Frontiers in immunology 37 32391006
2016 CXCR2 signaling regulates KRAS(G¹²D)-induced autocrine growth of pancreatic cancer. Oncotarget 37 26771140
2014 Host Cxcr2-dependent regulation of mammary tumor growth and metastasis. Clinical & experimental metastasis 37 25511644
2019 Interleukin-8 promotes cell migration via CXCR1 and CXCR2 in liver cancer. Oncology letters 36 31516616
2006 CXCR2--the receptor to hit? Drug news & perspectives 36 17299604
2016 TNF-α augments CXCR2 and CXCR3 to promote progression of renal cell carcinoma. Journal of cellular and molecular medicine 35 27297979
2023 The role of CXCL1/CXCR2 axis in neurological diseases. International immunopharmacology 34 37247498
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
2000 Expression of the chemokine receptor CXCR2 in normal and neoplastic neuroendocrine cells. Archives of pathology & laboratory medicine 34 10747307
2023 Expanding role of CXCR2 and therapeutic potential of CXCR2 antagonists in inflammatory diseases and cancers. European journal of medicinal chemistry 33 36780833
2020 CXCL5-CXCR2 signaling is a senescence-associated secretory phenotype in preimplantation embryos. Aging cell 33 32959976
2019 Secreted nuclear protein DEK regulates hematopoiesis through CXCR2 signaling. The Journal of clinical investigation 33 31107242
2014 Regulation of CXCR2 expression and function by a disintegrin and metalloprotease-17 (ADAM17). Journal of leukocyte biology 33 25412626
2020 KLF2 regulates neutrophil migration by modulating CXCR1 and CXCR2 in asthma. Biochimica et biophysica acta. Molecular basis of disease 32 32800946
2017 The Chemokine Receptor CXCR2 Supports Nociceptive Sensitization after Traumatic Brain Injury. Molecular pain 32 28845733
2021 Host Cxcr2-Dependent Regulation of Pancreatic Cancer Growth, Angiogenesis, and Metastasis. The American journal of pathology 30 33453178
2020 CXCL1/CXCR2 Paracrine Axis Contributes to Lung Metastasis in Osteosarcoma. Cancers 30 32079335
2019 Human Brain Endothelial CXCR2 is Inflammation-Inducible and Mediates CXCL5- and CXCL8-Triggered Paraendothelial Barrier Breakdown. International journal of molecular sciences 30 30704100
2017 Chemokine CXCL7 Heterodimers: Structural Insights, CXCR2 Receptor Function, and Glycosaminoglycan Interactions. International journal of molecular sciences 30 28368308
2021 Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma. Cells 28 34831316
2019 CXCR2 Blockade Mitigates Neural Cell Injury Following Preclinical Chorioamnionitis. Frontiers in physiology 28 31001130
2006 Cbl and Akt regulate CXCL8-induced and CXCR1- and CXCR2-mediated chemotaxis. International immunology 28 16798838
2023 Small molecule antagonist of CXCR2 and CXCR1 inhibits tumor growth, angiogenesis, and metastasis in pancreatic cancer. Cancer letters 26 37062329
2020 Selective blocking of CXCR2 prevents and reverses atrial fibrillation in spontaneously hypertensive rats. Journal of cellular and molecular medicine 25 32812337
2019 Cell-specific regulatory effects of CXCR2 on cholestatic liver injury. American journal of physiology. Gastrointestinal and liver physiology 25 31604030
2024 Non-homogenous intratumor ionizing radiation doses synergize with PD1 and CXCR2 blockade. Nature communications 24 39397001
2019 Tick saliva protein Evasin-3 modulates chemotaxis by disrupting CXCL8 interactions with glycosaminoglycans and CXCR2. The Journal of biological chemistry 24 31235521
2011 IQGAP1 is a novel CXCR2-interacting protein and essential component of the "chemosynapse". PloS one 24 21876773
2008 Induction of CXCR2 receptor by peroxisome proliferator-activated receptor gamma in human macrophages. Arteriosclerosis, thrombosis, and vascular biology 24 18292390
2009 CXCR2 and RET single nucleotide polymorphisms in pancreatic cancer. World journal of surgery 23 19057948
2020 Circ_0000215 Increases the Expression of CXCR2 and Promoted the Progression of Glioma Cells by Sponging miR-495-3p. Technology in cancer research & treatment 21 33089764
2019 CXCR2: A Novel Mediator of Mammary Tumor Bone Metastasis. International journal of molecular sciences 21 30871004
2022 Hyperactive immature state and differential CXCR2 expression of neutrophils in severe COVID-19. Life science alliance 20 36622345
2024 Neutrophils Recruited by NKX2-1 Suppression via Activation of CXCLs/CXCR2 Axis Promote Lung Adenocarcinoma Progression. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 19 39113226
2022 CXCR2 intrinsically drives the maturation and function of neutrophils in mice. Frontiers in immunology 19 36311783
2014 CXCR2 modulators: a patent review (2009 - 2013). Expert opinion on therapeutic patents 19 24555661

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