Affinage

CX3CL1

Fractalkine · UniProt P78423

Length
397 aa
Mass
42.2 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CX3CL1 (fractalkine) is a transmembrane chemokine that functions as both a membrane-anchored adhesion molecule and, after ADAM10/ADAM17-mediated ectodomain shedding followed by γ-secretase cleavage, a soluble chemoattractant for CX3CR1-expressing monocytes, NK cells, T cells, and microglia (PMID:15067194, PMID:17467666, PMID:25253723). Membrane-bound CX3CL1 mediates firm leukocyte adhesion through transmembrane domain-driven homo-oligomerization and regulates microglial phagocytosis via p38 MAPK, whereas soluble CX3CL1 is the dominant neuroprotective isoform that suppresses microglial activation, rescues hippocampal LTP and adult neurogenesis, and inhibits NLRP3 inflammasome-driven pyroptosis through NF-κB suppression (PMID:32494000, PMID:25209291, PMID:32410624, PMID:35461837). Sequential secretase processing also releases an intracellular domain (CX3CL1-ICD) that translocates to the nucleus and activates TGF-β2/3–Smad2/3 signaling to promote neurogenesis independently of CX3CR1 (PMID:31209068, PMID:31822518). In cancer, shed CX3CL1 signals through CX3CR1-coupled Src/FAK, PI3K/AKT, and RhoA pathways to drive tumor cell migration, metastasis, and immune cell trafficking in the tumor microenvironment (PMID:30066854, PMID:32319605, PMID:38280480).

Mechanistic history

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

    Establishing that CX3CL1 is a functional chemoattractant for microglia and mediates NK cell trafficking in vivo resolved the question of which immune cell types respond to fractalkine signaling in physiological contexts.

    Evidence Microglial chemotaxis assay plus human brain immunohistochemistry; in vivo NK clearance assay with anti-CX3CL1/CX3CR1 blocking antibodies in mice

    PMID:14533779 PMID:14698146

    Open questions at the time
    • Downstream signaling cascades in responding microglia and NK cells not defined
    • Relative contributions of soluble versus membrane-bound forms to NK trafficking unclear
  2. 2004 High

    Demonstrating that CX3CL1 exists as both a membrane-anchored adhesion molecule and a proteolytically released chemoattractant, with expression regulated by inflammatory cytokines, established the dual-function paradigm central to all subsequent mechanistic work.

    Evidence Cell stimulation, protein expression, and leukocyte adhesion assays in endothelial cells

    PMID:15067194

    Open questions at the time
    • Identity of the sheddase(s) not yet determined
    • Relative functional importance of soluble versus membrane forms unknown
  3. 2005 High

    Revealing that surface CX3CL1 undergoes SNARE-dependent recycling through a juxtanuclear compartment answered how cells maintain a dynamic surface pool available for both adhesion and shedding.

    Evidence Live-cell GFP-CX3CL1 imaging, VAMP-3/syntaxin-13 perturbation by tetanus toxin and dominant-negative alleles

    PMID:15774461

    Open questions at the time
    • Signals that regulate the recycling rate are undefined
    • Whether recycling compartment identity differs across cell types is untested
  4. 2007 High

    Identifying ADAM10 as the α-secretase and γ-secretase (presenilin-dependent) as the subsequent intramembrane protease defined the sequential cleavage cascade generating both soluble CX3CL1 and intracellular C-terminal fragments.

    Evidence Pharmacological inhibitor panel and presenilin 1/2-deficient cell lines with CTF detection

    PMID:17467666

    Open questions at the time
    • Biological function of the intracellular CTF was unknown
    • Relative contributions of ADAM10 versus ADAM17 in different tissues not resolved
  5. 2008 High

    Showing that thrombin/PAR1 induces endothelial CX3CL1 via NF-κB and that membrane-bound CX3CL1 triggers monocyte CCL2 release linked the coagulation cascade to CX3CL1-dependent vascular inflammation.

    Evidence PAR1 agonist/antagonist, IKK inhibitor, dominant-negative IκBα, co-culture and transendothelial migration assays in HUVECs

    PMID:18436581

    Open questions at the time
    • In vivo relevance in thrombotic disease models not tested
    • Whether soluble versus membrane CX3CL1 differentially triggers CCL2 undefined
  6. 2012 High

    Isoform-selective genetic rescue in CX3CL1-knockout mice proved that soluble CX3CL1 is the neuroprotective isoform in Parkinson's disease models, while membrane-bound CX3CL1 is dispensable for dopaminergic neuron survival.

    Evidence AAV delivery of obligate soluble vs. membrane-bound CX3CL1 into CX3CL1−/− mice; MPTP model with behavioral, histological, and cytokine readouts

    PMID:23077045

    Open questions at the time
    • CX3CR1-downstream signaling mediating neuroprotection not identified
    • Whether isoform specificity holds in other neurodegenerative contexts was unknown
  7. 2013 High

    In cancer biology, demonstrating that CX3CL1 promotes breast cancer growth through ErbB receptor transactivation and that its genetic deletion delays HER2/neu tumorigenesis placed CX3CL1 as a tumor-promoting factor in ErbB-dependent contexts.

    Evidence CX3CL1-KO crossed with HER2/neu and PyMT tumor mouse models; ErbB transactivation and EMT assays

    PMID:23720051

    Open questions at the time
    • Molecular identity of the ErbB ligand shed downstream of CX3CL1 not identified
    • Whether CX3CL1 acts on tumor cells directly or through stroma was not fully resolved
  8. 2014 High

    Two discoveries clarified how membrane topology controls CX3CL1 shedding and how each isoform has distinct CNS functions: cortical actin confines CX3CL1 away from ADAM10 to limit constitutive cleavage, and the membrane-bound (not soluble) form regulates microglial phagocytosis of Aβ via p38 MAPK.

    Evidence Single-particle tracking/PALM-STORM with actin disruption; genetic crosses of APPPS1 mice with CX3CL1-KO and soluble CX3CL1 transgenics

    PMID:25209291 PMID:25253723

    Open questions at the time
    • Structural basis for actin-CX3CL1 confinement unknown
    • How membrane CX3CL1 selectively activates p38 in microglia not resolved
  9. 2017 Medium

    Showing that N-terminal pyroglutamate modification by glutaminyl cyclase is required for full CX3CL1 signaling potency revealed a post-translational maturation step controlling chemokine bioactivity.

    Evidence Mass spectrometry confirming pGlu modification; QPCT RNAi; ERK1/2, Akt, p38 phosphorylation assays in SMCs and ECs

    PMID:28739588

    Open questions at the time
    • In vivo relevance of pGlu modification not tested
    • Whether pGlu differentially affects soluble vs. membrane CX3CL1 is unknown
  10. 2019 High

    The discovery that the γ-secretase-released intracellular domain (CX3CL1-ICD) translocates to the nucleus and activates TGF-β2/3–Smad2/3 signaling to drive neurogenesis independently of CX3CR1 established a 'back-signaling' mechanism analogous to Notch, fundamentally expanding CX3CL1's functional repertoire.

    Evidence CX3CL1-ct overexpression in 5xFAD mice; neuron-specific Smad2 knockout abrogating neurogenic effect; RNA-seq; PS19 tau model rescue with Smad2 epistasis

    PMID:31209068 PMID:31822518

    Open questions at the time
    • Nuclear targets of CX3CL1-ICD beyond TGF-β2/3 not identified
    • Whether ICD signaling occurs in non-neuronal tissues unknown
    • Structural basis for ICD nuclear import not defined
  11. 2019 High

    Soluble CX3CL1 gene therapy preserves cone photoreceptors across multiple retinitis pigmentosa models even after near-complete microglial depletion, demonstrating that CX3CL1's retinal neuroprotection involves transcriptional reprogramming of residual microglia rather than requiring normal microglial numbers.

    Evidence AAV8-sCX3CL1 in three RP mouse strains; ERG; pharmacological microglia depletion; RNA-seq of residual microglia

    PMID:31036641

    Open questions at the time
    • Identity of the protective transcriptional program in reprogrammed microglia not fully resolved
    • Whether other glial cells contribute to the rescue is untested
  12. 2020 High

    Demonstrating that membrane CX3CL1 forms homo-oligomers of 3–7 monomers via its transmembrane domain and that oligomerization is required for adhesive function provided the structural basis for the membrane-anchored adhesion phenotype.

    Evidence Native gel electrophoresis, single-molecule fluorescence, FRAP in lipid bilayers, TM domain peptide inhibition

    PMID:32494000

    Open questions at the time
    • Atomic-resolution structure of the oligomer not available
    • Whether oligomerization modulates shedding efficiency is untested
  13. 2020 Medium

    In metastatic cancer, shed CX3CL1 was shown to activate Src/FAK, PI3K/AKT, and RhoA/ROCK2 signaling through CX3CR1 on tumor cells, with ADAM17-mediated shedding from bone marrow endothelium driving spinal metastasis of prostate and hepatocellular carcinoma.

    Evidence CX3CR1 overexpression/knockdown; kinase inhibitor panels; CX3CL1 neutralization; in vivo spinal metastasis models

    PMID:30066854 PMID:32319605

    Open questions at the time
    • Whether these pathways are independent or form a linear cascade is unclear
    • Clinical relevance in human metastatic samples not validated
  14. 2022 Medium

    Establishing that CX3CL1 inhibits NLRP3 inflammasome assembly and GSDMD-dependent microglial pyroptosis via NF-κB suppression in ischemic stroke identified a specific anti-inflammatory mechanism beyond general microglial suppression.

    Evidence MCAO mouse model; OGD/R BV2 cells; intracerebroventricular CX3CL1; NLRP3/GSDMD western blot; NF-κB activation assay

    PMID:35461837

    Open questions at the time
    • Direct molecular target of CX3CL1 upstream of NF-κB suppression not identified
    • Whether soluble or membrane form mediates this effect in vivo not distinguished
  15. 2024 Medium

    Recent work placed CX3CL1 at the intersection of tumor metabolism and immune evasion: lactate/GPR81 signaling upregulates CX3CL1 to recruit Tregs in gastric cancer, and YTHDF2-dependent m6A stabilization of CX3CL1 mRNA recruits CD8+ T cells to suppress liver tumors, revealing context-dependent pro- and anti-tumor immune roles.

    Evidence GPR81 knockdown with Treg flow cytometry in humanized mice; liver-specific Ythdf2 KO with m6A-seq, RNA stability, and CD8+ T cell analysis

    PMID:38419759 PMID:39237909

    Open questions at the time
    • How the same chemokine recruits immunosuppressive Tregs in one context and cytotoxic CD8+ T cells in another is not mechanistically resolved
    • Post-transcriptional regulation of CX3CL1 in non-hepatic cancers not examined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic structure of CX3CL1 transmembrane oligomers, the full nuclear interactome of CX3CL1-ICD, why soluble and membrane-bound isoforms activate distinct downstream pathways through the same receptor CX3CR1, and how CX3CL1 exerts opposing immune effects (immunosuppressive vs. immunostimulatory) in different tumor microenvironments.
  • No high-resolution structure of full-length or oligomeric CX3CL1
  • Nuclear binding partners of CX3CL1-ICD beyond Smad2/3 pathway undefined
  • Mechanism distinguishing CX3CR1-dependent vs. CX3CR1-independent signaling outputs incompletely characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 6 GO:0098631 cell adhesion mediator activity 5 GO:0140110 transcription regulator activity 2
Localization
GO:0005576 extracellular region 5 GO:0005886 plasma membrane 5 GO:0031410 cytoplasmic vesicle 2 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 9 R-HSA-162582 Signal Transduction 8 R-HSA-1643685 Disease 5 R-HSA-1500931 Cell-Cell communication 4 R-HSA-1266738 Developmental Biology 2 R-HSA-5357801 Programmed Cell Death 1
Partners
ADAM10ADAM17CX3CR1PSEN1SMAD2STX13VAMP3

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 CX3CL1 is synthesized in endothelial cells as a transmembrane protein; the N-terminal chemokine domain is proteolytically cleaved and secreted as a soluble chemoattractant, while the membrane-bound form acts as an adhesion molecule for CX3CR1-expressing leukocytes (monocytes and lymphocytes). Expression is induced by TNF-α, IL-1, LPS, and IFN-γ, and inhibited by soluble IL-6Rα, 15-deoxy-Δ(12,14)-PGJ2, and hypoxia. Cell stimulation assays, protein expression analysis, functional adhesion assays in endothelial cells Journal of atherosclerosis and thrombosis High 15067194
2007 CX3CL1 transmembrane chemokine is sequentially processed by α-secretase activity (ADAM10, cleaving at multiple sites) and subsequently by γ-secretase (but not β-secretase), generating C-terminal fragments (CTFs) analogous to Notch/E-cadherin processing. This proteolytic cascade releases soluble CX3CL1 and produces intracellular CTFs. Inhibitor studies (ADAM10/γ-secretase/β-secretase/proteasome inhibitors), presenilin 1/2-deficient cell lines, CX3CL1 constructs C-terminally fused to 2Z-tag for CTF detection Biochemical and biophysical research communications High 17467666
2005 Cell surface CX3CL1 is in dynamic equilibrium with a juxtanuclear intracellular storage compartment distinct from conventional endosomes. Internalized CX3CL1 is recycled back to the plasma membrane via a SNARE-mediated mechanism involving syntaxin-13 and VAMP-3; cleavage of VAMP-3 by tetanus toxin or dominant-negative syntaxin-13 blocks this recycling. Live-cell fluorescence imaging of GFP-tagged CX3CL1, co-localization with SNARE proteins, tetanus toxin treatment, dominant-negative allele expression, subcellular fractionation The Journal of biological chemistry High 15774461
2006 In polarized renal tubular epithelial cells, CX3CL1 is targeted exclusively to the apical membrane and subapical vesicles. Apical targeting depends on N-linked glycosylation (not the intracellular domain, O-glycosylation, or lipid raft association). CX3CL1 is immobile in the apical membrane (FRAP) and is not directly actin-cytoskeleton-associated. Apical CX3CL1 promotes adhesion of CX3CR1-expressing leukocytes to the luminal surface. FRAP, immunofluorescence of polarized MDCK cells expressing GFP-CX3CL1, N-glycosylation and cholesterol depletion experiments, leukocyte adhesion assay, human biopsy immunohistochemistry Journal of the American Society of Nephrology High 17151328
2014 The cortical actin cytoskeleton confines CX3CL1 within restricted membrane domains, sequestering it from ADAM10 and limiting constitutive proteolytic cleavage. Disruption of actin by cytochalasin D reduces CX3CL1 confinement, increases CX3CL1-ADAM10 co-localization, and promotes soluble CX3CL1 release. Single-particle tracking, subdiffraction fluorescence imaging (PALM/STORM), pharmacological actin disruption, ADAM10 co-localization quantification Molecular biology of the cell High 25253723
2008 Thrombin induces CX3CL1 expression in human umbilical vein endothelial cells (HUVECs) via PAR1 activation and downstream NF-κB signaling. Membrane-anchored CX3CL1 induced by thrombin promotes monocyte adhesion to endothelium and triggers monocyte CCL2 release, potentiating transendothelial migration. Recombinant soluble CX3CL1 ectodomain alone induces CCL2 release from monocytes. RT-PCR, Western blot, flow cytometry, EMSA, ELISA; PAR1-activating peptide, PAR1 antagonist SCH 79797, IKK inhibitor, dominant-negative IκBα; co-culture and transendothelial migration assays Journal of leukocyte biology High 18436581
2012 Only the soluble isoform of CX3CL1 (not membrane-bound) provides neuroprotection in an MPTP mouse model of Parkinson's disease, reducing motor impairment, dopaminergic neuron loss, microglial activation, and pro-inflammatory cytokine release. The membrane-bound isoform was indistinguishable from GFP controls. AAV-mediated delivery of synthetic permanently soluble vs. obligate membrane-bound CX3CL1 variants into substantia nigra of CX3CL1−/− mice; behavioral testing, immunohistochemistry, cytokine ELISA The Journal of neuroscience High 23077045
2014 Membrane-anchored CX3CL1 (not soluble isoform) regulates microglial phagocytosis of amyloid-β and neuronal tau phosphorylation in Alzheimer's mouse models via the p38 MAPK pathway. CX3CL1 deficiency reduces Aβ deposition but paradoxically enhances tau phosphorylation; transgenic soluble CX3CL1 expression does not rescue either phenotype. Genetic crosses of APPPS1 mice with CX3CL1-KO and soluble CX3CL1 transgenic mice; microglia isolation for transcript profiling; p38 MAPK phosphorylation assay; Aβ internalization in purified microglia The Journal of neuroscience High 25209291
2020 Soluble CX3CL1 rescues cognitive deficits, hippocampal LTP, and adult neurogenesis in CX3CL1-KO mice, while the obligate membrane-bound form only partially rescues spatial learning and does not rescue long-term memory or neurogenesis, demonstrating isoform-specific functions. AAV delivery of sFKN or mFKN to CX3CL1-KO mice; behavioral tests (Morris water maze, novel object recognition); hippocampal LTP electrophysiology; neurogenesis markers by immunostaining Journal of neuroinflammation High 32410624
2019 CX3CL1 C-terminal intracellular domain (CX3CL1-ICD), released after sequential α-, β-, and γ-secretase cleavage, translocates to the nucleus and enhances adult neurogenesis through the TGF-β2/3-Smad2/3 pathway. This 'back-signaling' is independent of CX3CR1 and reduces amyloid pathology and neuronal loss in 5xFAD mice. CX3CL1-ct overexpression in 5xFAD mice; Smad2 neuron-specific knockout; RNA-seq of neurons; morphological analysis; TGF-β2/3 and Smad2 protein measurements The Journal of experimental medicine High 31209068
2019 CX3CL1 overexpression in neurons enhances neurogenesis in subgranular and subventricular zones via a TGF-β2/TGF-β3-Smad2 pathway. Neuron-specific deletion of Smad2 abrogates this effect. In tau P301S (PS19) Alzheimer's mice, neuronal CX3CL1 overexpression rescues neurodegeneration and improves cognition. Transgenic CX3CL1-overexpressing mice crossed with PS19 and with Smad2-neuron-specific KO mice; neurogenesis quantification; cognitive/motor behavioral testing; TGF-β and Smad2 protein measurements The Journal of neuroscience High 31822518
2018 CX3CL1-CX3CR1 signaling regulates microglial repopulation in the adult retina: repopulation is slowed in CX3CR1-deficient mice and accelerated by exogenous CX3CL1 administration. Repopulating microglia (derived from residual microglia in central inner retina) fully restore microglial distribution, morphology, process surveillance, and synaptic maintenance. In vivo imaging, cell-fate mapping, CX3CR1-GFP reporter mice, exogenous CX3CL1 intravitreal delivery, microglial depletion model Science advances High 29750189
2016 CX3CL1-CX3CR1 signaling suppresses microglial phagocytosis and activation in the degenerating retina (rd10 RP model). CX3CR1 deficiency accelerates photoreceptor apoptosis and increases microglial phagocytosis; exogenous CX3CL1 delivery reduces microglial infiltration and improves photoreceptor survival and function. CX3CR1(GFP/GFP) rd10 mice; in vivo phagosome counting; in vitro phagocytosis rate assay with fluorescent beads; live-cell imaging of retinal explants; intravitreal CX3CL1 delivery Glia High 27314452
2013 CX3CL1 promotes breast cancer cell proliferation by transactivating ErbB receptors through proteolytic shedding of an ErbB ligand, inducing epithelial-to-mesenchymal transition. Genetic deletion of CX3CL1 delays mammary tumorigenesis in HER2/neu mice but not in polyoma middle T-antigen mice, placing CX3CL1 specifically in the ErbB signaling context. Adenoviral CX3CL1 overexpression in HER2/neu transgenic mice; CX3CL1 genetic knockout crossed with tumor models; in vitro proliferation and EMT assays; ErbB receptor transactivation assays Cancer research High 23720051
2013 CX3CL1 regulates nerve injury-induced pain hypersensitivity through the ERK5 signaling pathway: CX3CR1 blockade reduces ERK5 phosphorylation in the spinal cord after SNL, and antisense ERK5 knockdown reverses CX3CL1-induced hyperalgesia and spinal microglial activation. Spinal nerve ligation (SNL) rat model; intrathecal antisense oligonucleotide knockdown of ERK5; intrathecal CX3CR1 blocking antibody; ERK5 phosphorylation western blot; behavioral pain testing Journal of neuroscience research Medium 23361876
2008 CX3CL1 treatment of trophoblast cells regulates expression of adhesion molecules and extracellular matrix components including α-catenin (CTNNA1), ECM1, osteopontin (SPP1), integrin α6 (ITGA6), MMP12, and integrin β5 (ITGB5), and increases trophoblast adhesion to fibronectin, suggesting a mechanism for CX3CL1-driven directional trophoblast migration during implantation. Pathway-specific oligonucleotide arrays, qRT-PCR, fibronectin adhesion assay, immunohistochemistry of first-trimester implantation sites Biology of reproduction Medium 18367676
2003 CX3CR1 signaling in microglia induces chemotaxis in response to CX3CL1 (confirmed by chemotaxis assay). CX3CL1 is constitutively expressed by human CNS astrocytes in vivo and in vitro; CX3CR1 is expressed on both astrocytes and microglia. Chemotaxis assay, immunohistochemistry of human brain tissue, RT-PCR, in vitro astrocyte cultures with cytokine stimulation Journal of neuropathology and experimental neurology Medium 14533779
2017 N-terminal pyroglutamate (pGlu) modification of CX3CL1 by glutaminyl cyclase (QC/QPCT) or isoQC (QPCTL) is required for full biological activity: pGlu1-CX3CL1 induces significantly stronger phosphorylation of ERK1/2, Akt, and p38 kinases than immature Gln1-CX3CL1, and drives higher expression of CCL2, CX3CL1, and ICAM1 in vascular smooth muscle and endothelial cells. QPCT expression is co-regulated with CX3CL1 via NF-κB. Mass spectrometry to confirm pGlu formation; RNAi knockdown of QPCT; kinase phosphorylation assays; gene expression by RT-PCR; NF-κB pathway inhibition Bioscience reports Medium 28739588
2020 CX3CL1 forms homo-oligomers of 3–7 monomers driven by intrinsic properties of its transmembrane domain, and this oligomerization is required for its adhesive function. A transmembrane domain peptide of CX3CL1 inhibits both oligomerization and cell-to-cell adherence, while a scrambled peptide control does not. Native electrophoresis, single-molecule fluorescence kinetics, FRAP in cellular and acellular lipid environments, molecular modeling, transmembrane peptide inhibition assay Scientific reports High 32494000
2012 ERK pathway and metalloprotease sheddases (ADAM17 and MMP) are required for CX3CL1 release from pancreatic stellate cells. Ethanol synergistically increases CX3CL1 secretion by activating ERK and ADAM17; specific inhibitors of ERK, MMP, and ADAM suppress CX3CL1 release. ERK is associated with CX3CL1 transcription. RT-PCR, western blot, ELISA in PSCs; kinase and protease inhibitors; in vivo CP rat model (WBN/Kob) Laboratory investigation Medium 23147224
2012 Exogenous fractalkine/CX3CL1 protects striatal neurons from synergistic morphine and HIV-1 Tat-induced dendritic loss and death by acting on CX3CR1-expressing microglia. Fractalkine normalizes elevated microglial motility caused by Tat/morphine co-exposure and fails to protect neurons co-cultured with CX3CR1-null microglia, demonstrating that protection requires microglial CX3CR1. Wild-type neurons co-cultured with Cx3cr1-KO or wild-type mixed glia; time-lapse microscopy; exogenous CX3CL1 addition; anti-CX3CR1 blocking antibody; ELISA for TNF-α and CX3CL1 Molecular neurodegeneration High 22093090
2014 HIV-1 Tat protein suppresses CX3CR1 expression in microglia via NF-κB activation followed by YY1-mediated transcriptional repression, disrupting CX3CL1-CX3CR1 signaling (calcium mobilization, MAPK activation, and microglial migration in response to CX3CL1). Primary microglia and BV2 cells exposed to Tat; RT-PCR and western blot for CX3CR1; NF-κB pathway inhibition; YY1 binding site identification; calcium mobilization assay; MAPK phosphorylation; microglial migration assay Current HIV research Medium 24862326
2019 CX3CL1-CX3CR1 interaction mediates macrophage-mesothelial crosstalk in peritoneal fibrosis: mesothelial CX3CL1 engages macrophage CX3CR1, promoting TGF-β production in a positive feedback loop where macrophage IL-1β upregulates mesothelial CX3CL1 and TGF-β; TGF-β in turn upregulates CX3CR1 in monocytic cells. CX3CR1 deficiency reduces peritoneal fibrosis in vivo. Murine PD model; CX3CR1-KO mice; human PD patient biopsies; in vitro macrophage-mesothelial cell co-culture; TGF-β and CX3CL1 protein measurements Kidney international Medium 30948201
2021 CX3CL1 promotes M1 macrophage polarization and osteoclast differentiation through the NF-κB signaling pathway in ankylosing spondylitis. NF-κB inhibition (BAY-117082) or anti-CX3CL1 mAb blocks M1 polarization, inflammation, and osteoclastogenesis in vitro and alleviates disease in AS model mice. In vitro macrophage polarization and osteoclast differentiation assays; NF-κB inhibitor; anti-CX3CL1 mAb; AS model mice; western blot and ELISA for inflammatory markers Journal of translational medicine Medium 37626378
2018 CX3CL1 enhances prostate cancer spinal metastasis by activating the Src/FAK signaling pathway, dependent on EGFR Tyr992 phosphorylation. CX3CR1 overexpression promotes tumor cell proliferation, migration, invasion, and spinal metastasis in vivo; Src/FAK inhibitors block CX3CL1-induced migration. CX3CR1 overexpression and knockdown in prostate cancer cells; kinase inhibitor assays; phosphorylation western blot; in vivo spinal metastasis mouse model International journal of oncology Medium 30066854
2012 Shear stress reduces TNFα-induced endothelial CX3CL1 expression and CX3CL1-dependent monocyte adhesion. Under low shear stress, transmembrane CX3CL1 mediates monocyte arrest on endothelium (blocked by neutralizing anti-CX3CL1 antibody); physiological shear stress abrogates this response. Endothelial cells (arterial, venous, microvascular) under controlled flow; TNFα stimulation; anti-CX3CL1 neutralizing antibody; monocyte THP-1 adhesion assay; CX3CL1 expression by western blot and immunofluorescence Mediators of inflammation Medium 28522896
2003 CX3CL1 is required for in vivo NK cell activity: antibody blockade of CX3CL1 or CX3CR1 reduces NK-mediated tumor cell clearance by 4–5-fold in mice without affecting in vitro NK cytolytic activity. CX3CR1 blockade inhibits NK cell adhesion to activated endothelium, indicating that CX3CL1 regulates NK cell extravasation/trafficking. In vivo NK clearance assay using radiolabeled YAC-1 cells; anti-CX3CL1 and anti-CX3CR1 blocking antibodies; in vitro NK cytotoxicity assay; NK adhesion assay to endothelial monolayers Cellular immunology Medium 14698146
2020 ADAM17-regulated shedding of CX3CL1 from bone marrow endothelial cells promotes hepatocellular carcinoma spinal metastasis. CX3CL1 activates Src/PTK2 signaling in HCC cells, subsequently activating PIK3CA/AKT1 and RHOA/ROCK2 pathways to drive invasion and migration. ADAM17 is activated by MAPK in BMECs, and neutralization of CX3CL1 inhibits BMEC-induced cancer cell invasion. Western blot for Src/FAK/PI3K/RHOA pathways; CX3CL1 neutralization; ADAM17 inhibition; in vivo mouse spinal metastasis model; CX3CR1 overexpression in HCC cells International journal of oncology Medium 32319605
2020 CX3CL1 directly induces platelet migration via CX3CR1/Syk/PI3K pathway components; hypoxia enhances platelet migration by upregulating CX3CL1 in HCC cells. Migrating platelets promote HCC cell apoptosis in vitro; CX3CL1 knockdown in HCC cells reduces platelet infiltration in an orthotopic HCC model. In vitro platelet migration assay; CX3CL1 knockdown in HCC cells; orthotopic HCC mouse model; mitochondrial membrane potential assay; apoptosis flow cytometry; pathway inhibition Molecular oncology Medium 32799418
2019 In retinitis pigmentosa, soluble CX3CL1 gene therapy (AAV8-sCX3CL1) significantly prolongs cone photoreceptor survival and improves visual function across three RP mouse strains. The mechanism does not require normal microglial numbers (pharmacological depletion of ~99% of microglia does not abrogate the effect), and RNA-seq reveals marked transcriptional changes in residual microglia. Subretinal AAV8-sCX3CL1 injection in three RP mouse strains; ERG functional testing; cone survival quantification; microglia pharmacological depletion; RNA-seq of microglia Proceedings of the National Academy of Sciences High 31036641
2024 Platelet-derived TLR4/NF-κB signaling upregulates ADAM10 in HCC tumor cells; ADAM10 then sheds CX3CL1, which acts on CX3CR1 to induce EMT and activate RhoA signaling, promoting lung metastasis. Knockdown of tumor cell TLR4 or ADAM10 inhibition prevents platelet-augmented tumor invasion. TLR4/ADAM10 knockdown in HCC cells; NF-κB pathway analysis; CX3CL1 shedding assay; RhoA signaling western blot; in vivo lung metastasis mouse model with platelet co-injection Cancer letters Medium 38280480
2022 CX3CL1 inhibits NLRP3 inflammasome-induced microglial pyroptosis and suppresses NF-κB signaling, thereby reducing IL-1β and IL-18 expression in ischemic stroke models (MCAO in vivo and OGD/R in vitro). Exogenous rCX3CL1 reduces GSDMD-dependent pyroptosis and decreases infarct volume. MCAO mouse model; OGD/R BV2 cells; intracerebroventricular CX3CL1 injection; NLRP3 and GSDMD western blot; NF-κB activation assay; ELISA for cytokines; immunostaining Life sciences Medium 35461837
2024 In hepatocytes, YTHDF2 (an m6A reader) stabilizes Cx3cl1 mRNA in an m6A-dependent manner downstream of OXA-activated cGAS-STING signaling, promoting CX3CL1 production that recruits CD8+ T cells to suppress liver tumor growth. Liver-specific Ythdf2 knockout reduces CX3CL1, CD8+ T cell infiltration, and anti-tumor immunity. Liver-specific Ythdf2 KO tumor-bearing mice; m6A-seq; RNA stability assay; CX3CL1 ELISA; CD8+ T cell flow cytometry; cGAS-STING pathway analysis Molecular cancer Medium 39237909
2024 In gastric cancer, lactate acts via GPR81 to upregulate CX3CL1 expression, which recruits regulatory T cells (Tregs) into the tumor microenvironment to suppress CD8+ T cell function. GPR81 deficiency reduces CX3CL1 and Treg infiltration, inhibiting tumor progression. In vitro lactate/GPR81 signaling assays; GPR81 knockdown; CX3CL1 ELISA; Treg and CD8+ T cell flow cytometry; humanized mouse model Oncoimmunology Medium 38419759

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Microglia and Aging: The Role of the TREM2-DAP12 and CX3CL1-CX3CR1 Axes. International journal of molecular sciences 216 29361745
2020 The Impact of the CX3CL1/CX3CR1 Axis in Neurological Disorders. Cells 202 33065974
2014 Modulating neurotoxicity through CX3CL1/CX3CR1 signaling. Frontiers in cellular neuroscience 186 25152714
2005 Induction of CX3CL1 expression in astrocytes and CX3CR1 in microglia in the spinal cord of a rat model of neuropathic pain. The journal of pain 170 15993821
2016 Microglial phagocytosis and activation underlying photoreceptor degeneration is regulated by CX3CL1-CX3CR1 signaling in a mouse model of retinitis pigmentosa. Glia 168 27314452
2021 CX3CL1/CX3CR1 signaling targets for the treatment of neurodegenerative diseases. Pharmacology & therapeutics 141 34492237
2004 Regulation of CX3CL1/fractalkine expression in endothelial cells. Journal of atherosclerosis and thrombosis 128 15067194
2012 The soluble isoform of CX3CL1 is necessary for neuroprotection in a mouse model of Parkinson's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 116 23077045
2002 Genomic variability in Potato potyvirus Y (PVY): evidence that PVY(N)W and PVY(NTN) variants are single to multiple recombinants between PVY(O) and PVY(N) isolates. Archives of virology 115 11890528
2013 Chemokines and atherosclerosis: focus on the CX3CL1/CX3CR1 pathway. Acta pharmacologica Sinica 109 23974513
2018 Repopulating retinal microglia restore endogenous organization and function under CX3CL1-CX3CR1 regulation. Science advances 107 29750189
2014 Opposing effects of membrane-anchored CX3CL1 on amyloid and tau pathologies via the p38 MAPK pathway. The Journal of neuroscience : the official journal of the Society for Neuroscience 101 25209291
2017 Roles for the CX3CL1/CX3CR1 and CCL2/CCR2 Chemokine Systems in Hypoxic Pulmonary Hypertension. American journal of respiratory cell and molecular biology 97 28125278
2010 CCL2/CCR2 and CX3CL1/CX3CR1 chemokine axes and their possible involvement in age-related macular degeneration. Journal of neuroinflammation 95 21126357
2020 Fractalkine/CX3CL1 in Neoplastic Processes. International journal of molecular sciences 90 32466280
2021 Regulation and biological functions of the CX3CL1-CX3CR1 axis and its relevance in solid cancer: A mini-review. Journal of Cancer 84 33391453
2020 MicroRNA-195 prevents hippocampal microglial/macrophage polarization towards the M1 phenotype induced by chronic brain hypoperfusion through regulating CX3CL1/CX3CR1 signaling. Journal of neuroinflammation 82 32819407
2007 Sequential processing of the transmembrane chemokines CX3CL1 and CXCL16 by alpha- and gamma-secretases. Biochemical and biophysical research communications 82 17467666
2010 Role of CX3CR1/CX3CL1 axis in primary and secondary involvement of the nervous system by cancer. Journal of neuroimmunology 79 20630606
2013 CX3CL1 promotes breast cancer via transactivation of the EGF pathway. Cancer research 77 23720051
2019 CX3CL1-CX3CR1 interaction mediates macrophage-mesothelial cross talk and promotes peritoneal fibrosis. Kidney international 75 30948201
2002 Fractalkine (CX3CL1) and brain inflammation: Implications for HIV-1-associated dementia. Journal of neurovirology 75 12476352
2022 CX3CL1/CX3CR1 interaction protects against lipotoxicity-induced nonalcoholic steatohepatitis by regulating macrophage migration and M1/M2 status. Metabolism: clinical and experimental 72 35914622
2003 CX3CL1 and CX3CR1 expression in human brain tissue: noninflammatory control versus multiple sclerosis. Journal of neuropathology and experimental neurology 70 14533779
2005 Up regulated expression of fractalkine/CX3CL1 and CX3CR1 in patients with systemic sclerosis. Annals of the rheumatic diseases 69 15608300
2012 Altered expression of CX3CL1 in patients with epilepsy and in a rat model. The American journal of pathology 65 22464888
2010 CX3CR1/CX3CL1 axis negatively controls glioma cell invasion and is modulated by transforming growth factor-β1. Neuro-oncology 65 20511186
2012 Gabapentin reduces CX3CL1 signaling and blocks spinal microglial activation in monoarthritic rats. Molecular brain 64 22647647
2008 CX3CL1 and CCL14 regulate extracellular matrix and adhesion molecules in the trophoblast: potential roles in human embryo implantation. Biology of reproduction 63 18367676
2021 Fractalkine (CX3CL1) and Its Receptor CX3CR1: A Promising Therapeutic Target in Chronic Kidney Disease? Frontiers in immunology 62 34163473
2020 CX3CL1 Signaling in the Tumor Microenvironment. Advances in experimental medicine and biology 61 32060841
2018 CX3CL1/fractalkine enhances prostate cancer spinal metastasis by activating the Src/FAK pathway. International journal of oncology 58 30066854
2016 Fractalkine/CX3CL1 in rheumatoid arthritis. Modern rheumatology 55 27484962
2022 CX3CL1 inhibits NLRP3 inflammasome-induced microglial pyroptosis and improves neuronal function in mice with experimentally-induced ischemic stroke. Life sciences 54 35461837
2020 Fractalkine (CX3CL1) signaling and neuroinflammation in Parkinson's disease: Potential clinical and therapeutic implications. Pharmacological research 54 32445958
2013 CX3CL1/CX3CR1 regulates nerve injury-induced pain hypersensitivity through the ERK5 signaling pathway. Journal of neuroscience research 53 23361876
2019 Crosstalk between the CX3CL1/CX3CR1 Axis and Inflammatory Signaling Pathways in Tissue Injury. Current protein & peptide science 50 30843484
2020 Two forms of CX3CL1 display differential activity and rescue cognitive deficits in CX3CL1 knockout mice. Journal of neuroinflammation 48 32410624
2018 Plant Cell Wall Dynamics in Compatible and Incompatible Potato Response to Infection Caused by Potato Virus Y (PVYNTN). International journal of molecular sciences 48 29543714
2023 CX3CL1 promotes M1 macrophage polarization and osteoclast differentiation through NF-κB signaling pathway in ankylosing spondylitis in vitro. Journal of translational medicine 46 37626378
2019 Soluble CX3CL1 gene therapy improves cone survival and function in mouse models of retinitis pigmentosa. Proceedings of the National Academy of Sciences of the United States of America 46 31036641
2016 Therapeutic intervention of inflammatory/immune diseases by inhibition of the fractalkine (CX3CL1)-CX3CR1 pathway. Inflammation and regeneration 46 29259682
2024 Lactate/GPR81 recruits regulatory T cells by modulating CX3CL1 to promote immune resistance in a highly glycolytic gastric cancer. Oncoimmunology 44 38419759
2020 Pivotal Involvement of the CX3CL1-CX3CR1 Axis for the Recruitment of M2 Tumor-Associated Macrophages in Skin Carcinogenesis. The Journal of investigative dermatology 44 32179066
2017 CX3CL1/CX3CR1 Axis, as the Therapeutic Potential in Renal Diseases: Friend or Foe? Current gene therapy 43 29446734
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2019 Tenophages: a novel macrophage-like tendon cell population expressing CX3CL1 and CX3CR1. Disease models & mechanisms 41 31744815
2013 Fractalkine (CX3CL1) and its receptor CX3CR1 may contribute to increased angiogenesis in diabetic placenta. Mediators of inflammation 41 23956503
2019 Activated CX3CL1/Smad2 Signals Prevent Neuronal Loss and Alzheimer's Tau Pathology-Mediated Cognitive Dysfunction. The Journal of neuroscience : the official journal of the Society for Neuroscience 40 31822518
2024 CX3CL1 (Fractalkine)-CX3CR1 Axis in Inflammation-Induced Angiogenesis and Tumorigenesis. International journal of molecular sciences 39 38731899
2018 CD200-, CX3CL1-, and TREM2-mediated neuron-microglia interactions and their involvements in Alzheimer's disease. Reviews in the neurosciences 38 29729150
2013 CX3CL1 and CX3CR1 expression in tertiary lymphoid structures in salivary gland infiltrates: fractalkine contribution to lymphoid neogenesis in Sjogren's syndrome. Rheumatology (Oxford, England) 37 24324211
2005 Recycling of the membrane-anchored chemokine, CX3CL1. The Journal of biological chemistry 37 15774461
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2021 Human CD16+ monocytes promote a pro-atherosclerotic endothelial cell phenotype via CX3CR1-CX3CL1 interaction. Cardiovascular research 35 32717023
2020 ADAM17-regulated CX3CL1 expression produced by bone marrow endothelial cells promotes spinal metastasis from hepatocellular carcinoma. International journal of oncology 34 32319605
2019 The intracellular domain of CX3CL1 regulates adult neurogenesis and Alzheimer's amyloid pathology. The Journal of experimental medicine 34 31209068
2000 Mutational analysis of RET/GDNF/NTN genes in children with total colonic aganglionosis with small bowel involvement. American journal of medical genetics 34 10946353
2021 Orthopedic surgery-induced cognitive dysfunction is mediated by CX3CL1/R1 signaling. Journal of neuroinflammation 33 33858422
2011 Fractalkine/CX3CL1 protects striatal neurons from synergistic morphine and HIV-1 Tat-induced dendritic losses and death. Molecular neurodegeneration 33 22093090
2008 Thrombin-induced expression of endothelial CX3CL1 potentiates monocyte CCL2 production and transendothelial migration. Journal of leukocyte biology 33 18436581
2021 CX3CL1-CX3CR1 Signaling Deficiency Exacerbates Obesity-induced Inflammation and Insulin Resistance in Male Mice. Endocrinology 32 33765141
2014 HIV-1 Tat disrupts CX3CL1-CX3CR1 axis in microglia via the NF-κBYY1 pathway. Current HIV research 31 24862326
2014 CX3CL1/CX3CR1 and CCL2/CCR2 chemokine/chemokine receptor complex in patients with AMD. PloS one 31 25503251
2012 Arterial and venous endothelia display differential functional fractalkine (CX3CL1) expression by angiotensin-II. Arteriosclerosis, thrombosis, and vascular biology 31 23117657
2020 Entry and exit of chemotherapeutically-promoted cellular dormancy in glioblastoma cells is differentially affected by the chemokines CXCL12, CXCL16, and CX3CL1. Oncogene 30 32346064
2006 Expression and targeting of CX3CL1 (fractalkine) in renal tubular epithelial cells. Journal of the American Society of Nephrology : JASN 30 17151328
2003 The chemokine CX3CL1 regulates NK cell activity in vivo. Cellular immunology 30 14698146
2017 Genome-wide DNA methylation analysis of articular chondrocytes identifies TRAF1, CTGF, and CX3CL1 genes as hypomethylated in osteoarthritis. Clinical rheumatology 29 28470428
2010 Relevance of the CX3CL1/fractalkine-CX3CR1 pathway in vasculitis and vasculopathy. Translational research : the journal of laboratory and clinical medicine 29 20004358
2024 YTHDF2 in peritumoral hepatocytes mediates chemotherapy-induced antitumor immune responses through CX3CL1-mediated CD8+ T cell recruitment. Molecular cancer 28 39237909
2022 Structure and Function of Ligand CX3CL1 and its Receptor CX3CR1 in Cancer. Current medicinal chemistry 28 35770395
2023 Targeted inhibition of CX3CL1 limits podocytes ferroptosis to ameliorate cisplatin-induced acute kidney injury. Molecular medicine (Cambridge, Mass.) 27 37875838
2013 Interaction between CX3CL1 and CX3CR1 regulates vasculitis induced by immune complex deposition. The American journal of pathology 27 23470165
2007 Issues regarding gene therapy products for Parkinson's disease: the development of CERE-120 (AAV-NTN) as one reference point. Parkinsonism & related disorders 27 18267286
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2017 Shear Stress Counteracts Endothelial CX3CL1 Induction and Monocytic Cell Adhesion. Mediators of inflammation 26 28522896
2017 N-terminal pyroglutamate formation in CX3CL1 is essential for its full biologic activity. Bioscience reports 26 28739588
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2012 ERK pathway and sheddases play an essential role in ethanol-induced CX3CL1 release in pancreatic stellate cells. Laboratory investigation; a journal of technical methods and pathology 26 23147224
2008 Glial cross-talk by transmembrane chemokines CX3CL1 and CXCL16. Journal of neuroimmunology 26 18538418
2003 Human keratinocytes express fractalkine/CX3CL1. Journal of dermatological science 26 12727021
2016 Expression of Chemokine XCL2 and CX3CL1 in Lung Cancer. Medical science monitor : international medical journal of experimental and clinical research 25 27156946
2021 Potential biomarkers reflecting inflammation in patients with severe periodontitis: Fractalkine (CX3CL1) and its receptor (CX3CR1). Journal of periodontal research 24 33641164
2019 GABAAR α2-activated neuroimmune signal controls binge drinking and impulsivity through regulation of the CCL2/CX3CL1 balance. Psychopharmacology 23 31030249
2016 The role of CX3CL1 in fetal-maternal interaction during human gestation. Cell adhesion & migration 23 26745855
2012 CX3CL1 expression in the conjunctiva is involved in immune cell trafficking during toxic ocular surface inflammation. Mucosal immunology 23 22692452
2019 Regulation of CX3CL1 Expression in Human First-Trimester Decidual Cells: Implications for Preeclampsia. Reproductive sciences (Thousand Oaks, Calif.) 22 30606080
2003 Expression of CX3CL1/fractalkine by mesangial cells in vitro and in acute anti-Thy1 glomerulonephritis in rats. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 22 14605272
2019 Placental CX3CL1 is Deregulated by Angiotensin II and Contributes to a Pro-Inflammatory Trophoblast-Monocyte Interaction. International journal of molecular sciences 21 30717334
2014 Preliminary study correlating CX3CL1/CX3CR1 expression with gastric carcinoma and gastric carcinoma perineural invasion. World journal of gastroenterology 21 24764683
2014 Cytoskeletal confinement of CX3CL1 limits its susceptibility to proteolytic cleavage by ADAM10. Molecular biology of the cell 21 25253723
2024 Direct interaction of platelet with tumor cell aggravates hepatocellular carcinoma metastasis by activating TLR4/ADAM10/CX3CL1 axis. Cancer letters 20 38280480
2023 The Cytokine CX3CL1 and ADAMs/MMPs in Concerted Cross-Talk Influencing Neurodegenerative Diseases. International journal of molecular sciences 20 37175729
2020 CX3CL1 homo-oligomerization drives cell-to-cell adherence. Scientific reports 20 32494000
2018 Pharmacokinetics, Pharmacodynamics, and Safety of E6011, a Novel Humanized Antifractalkine (CX3CL1) Monoclonal Antibody: A Randomized, Double-Blind, Placebo-Controlled Single-Ascending-Dose Study. Journal of clinical pharmacology 20 30575978
2017 Naringin Protects Against High Glucose-Induced Human Endothelial Cell Injury Via Antioxidation and CX3CL1 Downregulation. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 20 28848146
2012 The transmembrane chemokines CXCL16 and CX3CL1 and their receptors are expressed in human meningiomas. Oncology reports 20 23229614
2005 Pro-sequence and Ca2+-binding: implications for folding and maturation of Ntn-hydrolase penicillin amidase from E. coli. Journal of molecular biology 19 15843029