Affinage

PF4

Platelet factor 4 · UniProt P02776

Length
101 aa
Mass
10.8 kDa
Annotated
2026-04-29
100 papers in source corpus 38 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PF4/CXCL4 is a platelet α-granule chemokine that functions as a pleiotropic immunomodulatory and profibrotic mediator, organizing innate immune responses, regulating hematopoietic stem cell quiescence, and driving pathological thrombosis through formation of antigenic complexes with polyanions. Released from platelets via a PKC- and Rac1-dependent regulated secretory pathway, PF4 tetramers form ultralarge complexes with heparin or cell-surface glycosaminoglycans that serve as neoantigens recognized by anti-PF4 IgG, activating platelets through both FcγRIIA and the thrombopoietin receptor c-Mpl (JAK2/STAT3/STAT5) to cause heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombocytopenia and thrombosis (VITT) (PMID:15304392, PMID:37883794, PMID:34851659). PF4 signals through multiple receptors in a cell-type-dependent manner—CXCR3-A/B on T cells, CCR1 on monocytes, integrins on endothelial cells, and chondroitin sulfate proteoglycans on myeloid cells—to polarize macrophages toward a CD163-low/MMP7+S100A8+ (M4) or profibrotic SPP1+ phenotype, amplify TLR9/TLR8-mediated innate immune activation by assembling nucleic acids into liquid crystalline complexes that engage TBK1-IKKε-IRF5 signaling, and directly induce endothelial-to-mesenchymal transition and organ fibrosis (PMID:18174362, PMID:29930254, PMID:19910578, PMID:31043596, PMID:35701499, PMID:34986347, PMID:36807143). In the bone marrow niche, megakaryocyte-derived PF4 maintains HSC quiescence and negatively regulates megakaryocyte maturation as an autocrine factor under RUNX1 transcriptional control (PMID:25326802, PMID:2523411, PMID:21129147).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1989 Medium

    Establishing PF4 as an autocrine regulator of megakaryocytopoiesis resolved whether platelet-derived factors feed back on their lineage of origin: PF4 specifically inhibits megakaryocyte maturation (not proliferation) and modulates growth-regulatory gene expression.

    Evidence In vitro megakaryocyte colony assays with recombinant PF4 and synthetic C-terminal peptide, Northern blots for c-myc/c-myb, in situ hybridization for Factor V mRNA

    PMID:2523411

    Open questions at the time
    • Single-lab finding without independent replication at the time
    • Receptor mediating the maturation-inhibitory effect was not identified
    • In vivo relevance of autocrine regulation not demonstrated
  2. 2000 High

    Demonstrating that MMP-9 proteolytically degrades PF4 established a mechanism for local chemokine inactivation at sites of neutrophil infiltration, distinguishing CXC from CC chemokine susceptibility to neutrophil proteases.

    Evidence In vitro protease digestion assay with purified neutrophil gelatinase B and recombinant PF4

    PMID:11023497

    Open questions at the time
    • In vivo relevance of MMP-9-mediated PF4 degradation not established
    • Cleavage sites not mapped at residue level
  3. 2004 High

    Solving the structural basis of HIT antigenicity revealed that PF4 tetramers form ultralarge complexes with heparin at a narrow stoichiometric ratio, and these complexes are the primary antigenic species that activate platelets via FcγRIIA-dependent antibody binding.

    Evidence Size-exclusion chromatography, electron microscopy, monoclonal antibody binding, PF4 mutation studies, platelet activation assays

    PMID:15304392

    Open questions at the time
    • Precise structural arrangement within ultralarge complexes not resolved at atomic level
    • Mechanism of neoepitope exposure on PF4 upon complex formation not determined
  4. 2005 High

    Multiple studies established that PF4/heparin complex immunogenicity requires T cell help (CD40-CD40L) and that platelet-surface PF4 forms antigenic complexes independently of soluble heparin, broadening the antigenic trigger beyond circulating PF4/heparin.

    Evidence Euthymic vs. athymic mouse immunization, transgenic hPF4 mouse model with anti-PF4/heparin antibody injection, platelet binding assays

    PMID:15845897 PMID:16304054

    Open questions at the time
    • Specific T cell epitopes on PF4/heparin complexes not identified
    • Whether platelet-surface PF4 complexes drive clinical HIT in humans not directly shown
  5. 2005 High

    Identifying CXCR3-B as the receptor through which PF4 skews T helper cytokines toward a TH2 profile (downregulating T-bet, upregulating GATA-3) resolved a paradox of opposing T cell effects between CXCL4 and CXCL10 despite shared use of CXCR3.

    Evidence Antigen-specific T cell lines, anti-CXCR3 neutralizing antibody, IL-5/IL-13 promoter-reporter assays, flow cytometry

    PMID:16337473

    Open questions at the time
    • Downstream signaling divergence between CXCR3-A and CXCR3-B not fully mapped
    • In vivo relevance of PF4-driven TH2 skewing not established
  6. 2007 High

    Demonstrating that PF4 is sorted to regulated secretory granules via its signal peptide (unlike constitutively secreted CXCL4L1) explained how platelet activation gates PF4 release into the microenvironment.

    Evidence Transfection in multiple cell types, confocal microscopy for subcellular localization, PKC stimulation assays, secretion kinetics comparison

    PMID:17218382

    Open questions at the time
    • Specific signal peptide residues responsible for sorting not mapped
    • Whether other granule-sorting machinery components are involved is unknown
  7. 2008 High

    Defining PF4's receptor repertoire on different cell types—CXCR3 via GAG presentation for T cell chemotaxis and integrins αvβ3/αvβ5/α5β1 for endothelial cell adhesion and migration—established that PF4 acts through context-dependent receptor engagement rather than a single canonical receptor.

    Evidence PTX inhibition, CXCR3 antagonist, GAG-deficient CHO cells, integrin-blocking antibodies, HUVEC adhesion/migration assays

    PMID:18174362 PMID:18648521

    Open questions at the time
    • Whether integrin binding is direct or GAG-mediated not fully resolved
    • Structural basis of PF4-integrin interaction unknown
  8. 2009 High

    Discovery that PF4 downregulates CD163 on macrophages in a GAG-dependent manner, blocking hemoglobin-haptoglobin scavenging and heme oxygenase-1 induction, established the M4 macrophage polarization phenotype with direct implications for atherosclerosis.

    Evidence Flow cytometry, chlorate GAG inhibition, heparin blocking, heme oxygenase-1 functional assay on monocyte-derived macrophages

    PMID:19910578

    Open questions at the time
    • Specific proteoglycan receptor on macrophages mediating PF4 signaling not identified
    • In vivo demonstration of M4 macrophage functional consequences limited
  9. 2010 High

    Genetic deletion of Cxcl4 protected mice from liver fibrosis across two injury models and PF4 directly stimulated hepatic stellate cell proliferation, establishing PF4 as a platelet-derived profibrotic mediator in parenchymal organs.

    Evidence Cxcl4−/− mice with CCl4 and thioacetamide injury, FACS for infiltrating cells, in vitro stellate cell stimulation

    PMID:20162727

    Open questions at the time
    • Receptor on hepatic stellate cells not identified
    • Whether PF4 acts directly on stellate cells or via intermediate cell types in vivo not fully resolved
  10. 2011 High

    Identification of RUNX1 as a direct transcriptional regulator of PF4 (binding two consensus sites on the PF4 promoter) connected PF4 expression to the master megakaryocyte transcription factor network.

    Evidence ChIP, EMSA, luciferase promoter reporter, siRNA knockdown and RUNX1 overexpression in HEL cells

    PMID:21129147

    Open questions at the time
    • Whether other transcription factors cooperate with RUNX1 at the PF4 locus not explored
    • Regulation of PF4 in non-megakaryocytic cells not addressed
  11. 2014 High

    Demonstrating that megakaryocyte-derived PF4 maintains HSC quiescence in the bone marrow niche—with Cxcl4−/− mice showing expanded, hyperproliferative HSCs—revealed a non-hemostatic stem cell regulatory function of PF4.

    Evidence 3D whole-mount imaging, megakaryocyte depletion, Cxcl4−/− phenotyping, exogenous CXCL4 injection, cell cycle assays

    PMID:25326802

    Open questions at the time
    • Receptor through which PF4 signals to HSCs not identified
    • Whether PF4 acts directly on HSCs or through niche intermediary cells not definitively resolved
  12. 2015 High

    Establishing Rac1 as the GTPase controlling PF4 secretion from activated platelets, and showing that released PF4 indirectly recruits neutrophils by inducing CXCL2 from alveolar macrophages, delineated a platelet-macrophage-neutrophil amplification circuit.

    Evidence Rac1 inhibitor (NSC23766) in vivo and in vitro, platelet depletion, CXCL4 immunoneutralization, CXCR2 antagonist

    PMID:26478565

    Open questions at the time
    • Whether Rac1 acts specifically on α-granule exocytosis or general granule secretion not dissected
    • Mechanism by which PF4 induces CXCL2 in macrophages not identified
  13. 2018 High

    Identification of CCR1 (not CXCR3) as the functional PF4 receptor on monocytes, with GAG-dependent presentation and PTX-sensitive signaling, resolved a long-standing question about how PF4 recruits myeloid cells.

    Evidence CCR1 transfectant migration, CCR1 antagonist blocking, chondroitinase ABC treatment, PTX inhibition, monocyte CCR1 endocytosis

    PMID:29930254

    Open questions at the time
    • Whether PF4 is a direct CCR1 ligand or requires GAG-mediated oligomerization for receptor activation not fully resolved
    • Structural basis of PF4-CCR1 interaction unknown
  14. 2019 High

    Discovery that PF4 organizes DNA into liquid crystalline complexes that amplify TLR9-dependent IFN-α production in pDCs—independently of CXCR3—established a novel innate immune amplification mechanism linking PF4 to autoimmune type I interferon signatures.

    Evidence Biophysical characterization of CXCL4-DNA complexes, TLR9 stimulation assays, CXCR3-KO controls, detection of complexes in SSc patient plasma

    PMID:31043596

    Open questions at the time
    • How PF4-DNA complexes are internalized into endosomes for TLR9 access not determined
    • Whether PF4-DNA complex formation occurs constitutively or only during tissue damage not established
  15. 2019 Medium

    Structural determination of PF4-CXCL12 heterodimers by NMR revealed a new mechanism for PF4 to antagonize CXCR4 signaling, blocking CXCL12-driven cancer cell migration through heterodimer sequestration.

    Evidence NMR spectroscopy of binding interface, cell migration assay, CXCR4 blocking antibody, PF4-derived interface peptide

    PMID:31785332

    Open questions at the time
    • Single-lab finding; in vivo relevance of PF4-CXCL12 heterodimers not demonstrated
    • Stoichiometry and affinity of heterodimer formation under physiological conditions not established
  16. 2021 High

    Cryo-EM and SPR demonstrated that adenovirus vaccine vectors (ChAdOx1, HAdV-D26, HAdV-C5) bind PF4 via electrostatic interactions, providing the structural mechanism for VITT neoantigen formation analogous to heparin-induced HIT complexes.

    Evidence Cryo-EM structure determination, electrostatic computational modeling, surface plasmon resonance binding

    PMID:34851659

    Open questions at the time
    • Whether adenovirus-PF4 binding in vivo leads directly to neoepitope exposure identical to HIT not confirmed
    • Atomic-resolution complex structure not available
  17. 2022 High

    Demonstrating that PF4 synergizes with TLR8 to repurpose TBK1-IKKε toward IRF5-dependent inflammatory gene activation (including NLRP3 inflammasome) with chromatin remodeling at de novo enhancers established PF4 as an epigenetic modifier of innate immune transcription.

    Evidence TBK1/IKKε inhibitors, siRNA knockdown, ATAC-seq/ChIP-seq, NLRP3 inhibition in human monocytes

    PMID:35701499

    Open questions at the time
    • Whether PF4-TLR8 synergy operates through direct receptor engagement or nucleic acid organization not resolved
    • In vivo relevance of TBK1-IKKε-IRF5 repurposing in disease settings not demonstrated
  18. 2022 High

    Genetic loss-of-function and gain-of-function studies across skin, lung, and heart established PF4 as a direct profibrotic mediator that induces endothelial-to-mesenchymal transition (EndMT) and collagen synthesis, extending the fibrotic role beyond liver.

    Evidence Cxcl4−/− mice, human CXCL4 overexpression, CXCL4 neutralization, in vitro EndMT assays, single-cell ligand-receptor analysis

    PMID:34986347

    Open questions at the time
    • Receptor mediating EndMT induction on endothelial cells not identified
    • Whether EndMT is the dominant fibrotic mechanism versus macrophage-mediated fibrosis not resolved
  19. 2023 High

    Single-nucleus RNA sequencing revealed that PF4 drives differentiation of SPP1+ profibrotic macrophages, and Cxcl4−/− mice lack this population and are protected from cardiac and renal fibrosis, unifying the macrophage-polarizing and profibrotic activities of PF4.

    Evidence snRNA-seq, Cxcl4−/− mouse models of heart and kidney injury, platelet depletion, in vitro macrophage differentiation

    PMID:36807143

    Open questions at the time
    • Signaling pathway from PF4 to SPP1 macrophage commitment not identified
    • Whether SPP1+ macrophage phenotype is reversible upon PF4 withdrawal unknown
  20. 2023 High

    Demonstrating that PF4 binds endothelial GAGs to increase leukocyte adhesion and vascular permeability independently of chemokine receptors provided a unifying mechanism for PF4's promiscuous, receptor-independent effects on vascular inflammation.

    Evidence Biophysical GAG binding assays, in vitro leukocyte adhesion and permeability assays, in vivo leukocyte recruitment, GAG sulfation modification experiments

    PMID:36640356

    Open questions at the time
    • Specific GAG sulfation patterns conferring PF4 selectivity not fully defined
    • Whether GAG-bound PF4 can simultaneously engage canonical receptors not tested
  21. 2024 High

    Identification of c-Mpl (thrombopoietin receptor) as a functional PF4 receptor on platelets that activates JAK2-STAT3/5 signaling resolved how PF4-containing immune complexes in VITT activate platelets through dual receptor engagement (FcγRIIA + c-Mpl).

    Evidence c-Mpl binding assay, JAK2 inhibition, STAT3/5 phosphorylation, platelet aggregation with PF4 and VITT sera

    PMID:37883794

    Open questions at the time
    • Structural basis of PF4-c-Mpl interaction not determined
    • Whether c-Mpl signaling contributes to non-VITT platelet responses to PF4 not explored
    • Relative contribution of FcγRIIA versus c-Mpl in clinical VITT not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • The receptor(s) through which PF4 maintains HSC quiescence and drives SPP1+ macrophage differentiation remain unidentified, and no integrated structural model explains how a single tetramer engages such diverse receptor classes in a context-dependent manner.
  • HSC-niche receptor for PF4 unknown
  • Structural basis of PF4 tetramer interaction with c-Mpl, CCR1, and integrins not resolved
  • In vivo relevance of PF4-nucleic acid complexes in autoimmune disease requires clinical validation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0008289 lipid binding 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-168256 Immune System 7 R-HSA-109582 Hemostasis 4 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2
Partners
CCR1CXCL12CXCR3FCGR2AMMP9MPLRUNX1
Complex memberships
CXCL4-CXCL12 heterodimerCXCL4-DNA liquid crystalline complexPF4-adenovirus complexPF4/heparin ultralarge complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 MMP-9 (neutrophil gelatinase B) degrades PF4/CXCL4 protein, demonstrating that PF4 is a proteolytic substrate of MMP-9, unlike CC chemokines RANTES and MCP-2 which are resistant. In vitro protease digestion assay with purified neutrophil gelatinase B and recombinant PF4 Blood High 11023497
2004 PF4 tetramers form ultralarge complexes (>670 kDa) with unfractionated heparin only over a narrow molar ratio (~1:1 PF4:heparin); these ultralarge complexes are more antigenic and more potent at activating platelets in an antibody/FcγRIIA-dependent manner. Formation of ultralarge complexes requires PF4 tetramers and does not occur with fondaparinux. Size-exclusion chromatography, electron microscopy, monoclonal antibody binding assay, platelet activation assay, PF4 mutation studies Blood High 15304392
2005 Platelet surface-bound PF4 forms antigenic complexes independently of soluble heparin, but heparin shifts the concentration of PF4 needed for optimal surface antigenicity to higher levels; the severity of thrombocytopenia correlates with platelet hPF4 expression levels in transgenic mice. In vitro platelet binding assays with recombinant human PF4, transgenic mouse model expressing different levels of human PF4, injection of monoclonal anti-PF4/heparin antibody (KKO) Blood High 16304054
2005 PF4/heparin complexes are T cell-dependent antigens; euthymic but not athymic mice develop anti-PF4/heparin autoantibodies with HIT-like properties after immunization with PF4/heparin complexes, establishing requirement for thymic T cells in antibody production. Mouse immunization model comparing euthymic vs. athymic mice; functional platelet activation assay; serological binding assays Blood High 15845897
2007 PF4/CXCL4 is stored in secretory granules and released in response to protein kinase C (PKC) activation via a regulated secretory pathway, whereas its non-allelic variant CXCL4L1 is constitutively secreted; this differential secretion is driven by the distinct signal peptide sequences. Transfection of different cell types, subcellular localization by immunofluorescence/confocal microscopy, PKC stimulation assays, comparison of secretion kinetics Blood High 17218382
2008 CXCL4 interacts with integrins αvβ3, αvβ5, and α5β1 on endothelial cells; immobilized CXCL4 supports endothelial cell spreading and migration through integrin-dependent mechanisms, while soluble CXCL4 inhibits integrin-dependent adhesion and migration. Cell adhesion assays using αvβ3-CHO transfectants, HUVEC adhesion/migration assays, integrin-blocking antibodies PloS one Medium 18648521
2008 CXCL4-induced migration of activated T lymphocytes is mediated by CXCR3 via Gαi-sensitive G-protein signaling; CXCL4 binds to CXCR3 primarily via glycosaminoglycans (GAGs) on the cell surface rather than direct high-affinity receptor binding, and both CXCR3-A and CXCR3-B isoforms mediate CXCL4-induced migration. Pertussis toxin inhibition, CXCR3 antagonist blocking, calcium flux assay, L1.2 transfectants expressing CXCR3-A or CXCR3-B, GAG-deficient CHO cell competition binding Journal of leukocyte biology High 18174362
2009 CXCL4 downregulates the hemoglobin scavenger receptor CD163 on human macrophages differentiated from monocytes, and this effect requires cell-surface glycosaminoglycans (GAGs); heparin neutralizes CXCL4 and prevents CD163 downregulation. CD163-negative CXCL4-induced macrophages cannot upregulate atheroprotective heme oxygenase-1 in response to hemoglobin-haptoglobin complexes. Flow cytometry, mRNA time-course analysis, chlorate (GAG synthesis inhibitor) pretreatment, heparin blocking, heme oxygenase-1 induction assay Circulation research High 19910578
2009 CXCL4 protects the antimicrobial peptide LL-37 from cleavage by mast cell beta-tryptase not by directly inhibiting the enzyme, but by destabilizing the active tetrameric form of beta-tryptase through antagonizing heparin, which is required for tryptase tetramer integrity. In vitro protease cleavage assay, beta-tryptase inhibitor studies, heparin competition assay, functional activity assays (degranulation, bactericidal, LPS neutralization) Journal of immunology High 19625657
2011 RUNX1 is a transcriptional regulator of PF4; RUNX1 binds to consensus sites at −1774/−1769 and −157/−152 on the PF4 promoter, and RUNX1 knockdown decreases PF4 promoter activity and protein levels while RUNX1 overexpression increases them. Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), luciferase reporter assay, siRNA knockdown, RUNX1 overexpression in HEL cells Journal of thrombosis and haemostasis High 21129147
2011 CXCL4 signaling through CXCR3-B involves Gs proteins, elevated cAMP, and p38 MAP kinase; signaling through chondroitin sulfate proteoglycans involves Src-family kinases, Syk, monomeric GTPases (including Rac2), sphingosine kinase 1, and MAP kinase family members, with biphasic activation kinetics. Pharmacological inhibitors, signaling pathway analysis in neutrophils and monocytes (reviewed from primary experimental literature) European journal of cell biology Medium 21295372
2012 PF4/heparin-antibody complexes induce tissue factor (TF) expression in monocytes and release of TF-positive microparticles via engagement of FcγRI and activation of the MEK1-ERK1/2 signaling pathway. Ex vivo monocyte stimulation with monoclonal anti-PF4/heparin antibody (KKO) and HIT patient plasma; TF expression by flow cytometry; FcγRI blocking; MEK1-ERK1/2 pathway inhibition Blood High 22394597
2011 ODSH (2-O, 3-O desulfated heparin), but not dabigatran or rivaroxaban, inhibits PF4 binding to platelets, displaces PF4/heparin complexes from platelet surfaces, and inhibits anti-PF4/heparin antibody binding and subsequent platelet activation by competing for PF4 binding. Gel-filtered platelet binding assay, PF4-transfected cell line displacement assay, platelet activation assay Blood High 22049520
2014 Megakaryocytes are the predominant source of CXCL4/PF4 in the bone marrow, and CXCL4 regulates HSC quiescence; CXCL4 injection reduces HSC numbers by increasing quiescence, while Cxcl4-/- mice show expanded HSC numbers and increased proliferation. 3D whole-mount imaging, selective MK depletion in vivo, Cxcl4-/- mouse phenotyping, CXCL4 injection, gene expression analysis, cell cycle assays Nature medicine High 25326802
2014 CXCL4-induced macrophages (M4) are specifically identified by co-expression of MMP7 and S100A8; CXCL4 upregulates both markers in a dose- and time-dependent manner, and this effect is blocked by heparin, implicating cell-surface glycosaminoglycans as the macrophage receptor mediating CXCL4 signaling. Transcriptomic analysis, qPCR, protein expression, heparin blocking, immunofluorescence of human atherosclerotic plaques Innate immunity Medium 24663337
2015 CD4 T cells are required for PF4/heparin-specific antibody production; depletion of CD4 T cells markedly impairs antibody induction, and B cells lacking CD40 show reduced PF4/heparin-specific antibody production, establishing T cell help via CD40-CD40L interaction as a critical mechanism. Anti-CD4 antibody depletion in mice, Rag1-/- reconstitution with B and T cell subsets, CD40-deficient B cells, PF4/heparin immunization challenge Blood High 25595736
2015 Platelet secretion of CXCL4 is Rac1-dependent; Rac1 inhibitor NSC23766 reduces CLP-enhanced plasma CXCL4 by 77% and abolishes PAR4 agonist-induced CXCL4 secretion from isolated platelets. CXCL4 indirectly promotes pulmonary neutrophilia by stimulating CXCL2 secretion from alveolar macrophages, which then drives neutrophil recruitment via CXCR2. Rac1 inhibitor in vivo and in vitro, platelet depletion, CXCL4 immunoneutralization, alveolar macrophage stimulation, CXCR2 antagonist in vivo British journal of pharmacology High 26478565
2016 CXCL4 and CXCR2 regulate hematopoietic stem/progenitor cell survival and self-renewal; CXCL4 knockdown decreases HSC colony-forming potential, and Cxcl4-/- mice show decreased HSC numbers and reduced self-renewal capacity in serial transplantation assays. siRNA knockdown of CXCL4 in human CD34+ cells, pharmacological CXCR2 inhibition, Cxcr2-/- and Cxcl4-/- mouse phenotyping, serial transplantation assays Blood High 27222476
2018 CXCL4 drives chemotaxis of monocytes via CCR1 (not CXCR3); CXCL4-induced migration and calcium responses are pertussis toxin-sensitive, require cell-surface glycosaminoglycan presentation, and CXCL4 induces CCR1 endocytosis on primary human monocytes. THP-1 migration assay, pertussis toxin treatment, chondroitinase ABC treatment, CCR1 transfectant migration, CCR1 antagonist blocking, primary human monocyte endocytosis assay Scientific reports High 29930254
2018 Polyreactive natural IgM initiates classical complement pathway activation on PF4/heparin complexes; depletion of IgM from plasma abrogates complement activation, and anti-C1q antibody prevents IgM-mediated complement activation, demonstrating classical pathway involvement. Plasma IgM depletion, proteomic correlation analysis, cord blood IgM addition, monoclonal polyreactive IgM assay, anti-C1q antibody blocking, C3c generation measurement Blood High 30309891
2019 CXCL4 assembles DNA into liquid crystalline complexes that amplify TLR9-mediated IFN-α production by plasmacytoid dendritic cells; this activity does not require CXCR3 and correlates with type I IFN signature in SSc blood; CXCL4-DNA complexes are present in vivo. Biophysical characterization of CXCL4-DNA complexes, TLR9 stimulation assays with pDCs, CXCR3-knockout controls, detection of complexes in patient plasma, immunofluorescence of skin pDCs Nature communications High 31043596
2019 CXCL4 inhibits macrophage phagocytic capacity by reducing CD36 levels through MMP-9-dependent and -independent signaling; CD36 neutralizing antibody did not have additive effect with CXCL4, establishing CD36 as the phagocytosis pathway through which CXCL4 acts. Ex vivo and in vitro phagocytosis assays, CD36 neutralizing antibody, exogenous CXCL4 infusion via mini-pump in MI mouse model Cardiovascular research Medium 30169632
2019 CXCL4 forms heterodimers with CXCL12; NMR spectroscopy identified the binding interface, and CXCL4-CXCL12 heterodimers inhibit CXCL12-driven breast cancer cell migration by blocking CXCR4 signaling. NMR spectroscopy, cell migration assay, CXCR4 blocking antibody, CXCL4-derived binding interface peptide Cellular signalling Medium 31785332
2019 Bacterial IdeS protease cleaves anti-PF4/heparin IgG at the hinge region, abolishing FcγRIIA binding without reducing binding to PF4/heparin complexes, and fully abolishes heparin-dependent platelet activation and tissue factor synthesis by monocytes; IdeS prevents thrombocytopenia in transgenic mice expressing human PF4 and FcγRIIA. IdeS cleavage of monoclonal and patient-derived anti-PF4/H IgG, FcγRIIA binding assay, platelet aggregation assay, TF mRNA synthesis, microfluidic channel fibrin formation, transgenic mouse model Blood High 30917957
2020 CXCL4 drives fibrosis through CIITA-mediated transcriptional reprogramming of monocyte-derived dendritic cells, inducing a pro-inflammatory and pro-fibrotic phenotype that directly triggers fibroblast activation and ECM production; CIITA inhibition mimics CXCL4 effects. Whole genome transcriptional and methylation profiling, gene regulatory network analysis, CIITA inhibition, myofibroblast differentiation assays Frontiers in immunology Medium 33042127
2021 ChAdOx1 adenovirus vector binds PF4 via electrostatic interaction; all three adenoviruses deployed as COVID-19 vaccine vectors (ChAdOx1, HAdV-D26, HAdV-C5) bind PF4, and stable PF4-adenovirus complexes form, confirmed by surface plasmon resonance using the ChAdOx1 cryo-EM structure for computational simulation. Cryo-EM structure determination, computational electrostatic simulations, surface plasmon resonance binding assay Science advances High 34851659
2021 C5a activation of C5aR1 on platelets induces preferential release of CXCL4/PF4, which acts as an antiangiogenic paracrine effector; platelet-specific C5aR1 deletion results in a proangiogenic phenotype, and interfering with the C5aR1-CXCL4 axis reverses the antiangiogenic effect of platelets. C5ar1-/- mice, platelet-specific C5aR1 deletion, in vitro endothelial migration/tube formation, CXCL4 neutralization, in vivo vascularization models Nature communications High 34099640
2022 CXCL4 synergizes with TLR8 to activate TBK1 and IKKε, which are repurposed toward an inflammatory response via coupling with IRF5, activating the NLRP3 inflammasome and selectively amplifying inflammatory gene transcription and IL-1β production while partially attenuating the interferon response; CXCL4+TLR8 costimulation induces chromatin remodeling and activates de novo enhancers at inflammatory genes. Pharmacological inhibitors of TBK1/IKKε, siRNA knockdown, ATAC-seq/ChIP-seq chromatin analysis, cytokine measurements, NLRP3 inhibition in human monocytes Nature communications High 35701499
2022 CXCL4 drives fibrosis directly in multiple organs; CXCL4-deficient mice are protected from skin, lung, and heart fibrosis, human CXCL4 overexpression aggravates bleomycin fibrosis, and CXCL4 directly induces myofibroblast differentiation and collagen synthesis in endothelial cells by stimulating endothelial-to-mesenchymal transition. Cxcl4-/- mice, human CXCL4 overexpression mouse model, CXCL4 neutralization, in vitro endothelial-to-mesenchymal transition assays, single-cell ligand-receptor analysis Cell reports High 34986347
2023 CXCL4 binds to glycosaminoglycan (GAG) sugars on proteoglycans within the endothelial extracellular matrix, resulting in increased leukocyte adhesion, increased vascular permeability, and non-specific recruitment of a range of leukocytes independently of chemokine receptors; GAG sulfation confers selectivity on chemokine localization. Biophysical binding assays, in vitro leukocyte adhesion and permeability assays, in vivo leukocyte recruitment models, GAG modification experiments Cell reports High 36640356
2023 CXCL4 drives profibrotic SPP1+ macrophage (Spp1 macrophage) differentiation; loss of Cxcl4 abrogates Spp1 macrophage differentiation and ameliorates fibrosis after heart and kidney injury; platelets are the primary in vivo source of CXCL4 driving this macrophage subtype. Single-nucleus RNA sequencing, Cxcl4-/- mouse models, platelet depletion, in vitro macrophage differentiation, ligand-receptor interaction analysis Cell reports High 36807143
2023 Platelets are activated by exercise and are required for exercise-induced hippocampal precursor cell proliferation in aged mice; increasing systemic levels of the platelet-derived CXCL4/PF4 ameliorates age-related regenerative and cognitive impairments in a hippocampal neurogenesis-dependent manner. Platelet depletion during exercise, systemic PF4 administration, hippocampal neurogenesis quantification, cognitive behavioral testing in aged mice Nature communications Medium 37587147
2024 PF4 binds and activates the thrombopoietin receptor c-Mpl on platelets, leading to JAK2 activation and phosphorylation of STAT3 and STAT5, which drives platelet aggregation; inhibition of c-Mpl-JAK2 pathway inhibits platelet aggregation to PF4 alone and to VITT immune complexes (PF4+VITT IgG); PF4-based immune complexes activate platelets through both FcγRIIA (Fc domain) and c-Mpl (PF4 moiety). c-Mpl binding assay on platelets, JAK2 inhibition, STAT3/5 phosphorylation analysis, platelet aggregation assays with PF4, VITT sera, and VITT IgG+PF4 combinations Blood High 37883794
1989 PF4 inhibits human megakaryocyte maturation (not proliferation) in vitro; a synthetic COOH-terminal PF4 peptide of 24 residues reproduces this effect; PF4 decreases Factor V mRNA levels in megakaryocytes and upregulates c-myc and c-myb, suggesting negative autocrine regulation of megakaryocytopoiesis. In vitro colony formation assay, cell number enumeration, in situ hybridization for Factor V mRNA, Northern blot for growth-regulated genes The Journal of clinical investigation Medium 2523411
2010 CXCL4 is a platelet-derived mediator of liver fibrosis; genetic deletion of Cxcl4 reduces liver damage, infiltration of neutrophils and CD8+ T cells, and expression of fibrosis-related genes (Timp-1, Mmp9, Tgf-β, IL-10); recombinant CXCL4 directly stimulates hepatic stellate cell proliferation, chemotaxis, and chemokine expression in vitro. Cxcl4-/- mouse models with CCl4 and thioacetamide injury, FACS for immune cell infiltration, in vitro stellate cell stimulation assays Hepatology High 20162727
2020 CXCL4 triggers monocytes and macrophages to produce PDGF-BB, which then activates dermal fibroblasts to produce ECM and inflammatory mediators; this CXCL4→PDGF-BB→fibroblast activation axis is abrogated by PDGF receptor inhibition with Crenolanib. Monocyte stimulation with CXCL4, PDGF-BB ELISA/Western blot, siRNA and Crenolanib PDGF-receptor inhibition, fibroblast ECM deposition and cytokine assays Journal of autoimmunity Medium 32284212
2022 CXCL4 production in plasmacytoid dendritic cells is driven by co-stimulation with hypoxia and TLR9 agonist via mitochondrial reactive oxygen species (mtROS) leading to stabilization of HIF-2α; blocking mtROS or HIF-2α attenuates CXCL4 production. pDC culture under hypoxia + TLR9 stimulation, mtROS inhibitors, HIF-1α and HIF-2α protein/gene analysis, HIF-2α siRNA, ELISA for CXCL4 Rheumatology (Oxford) Medium 34559222
2005 CXCL4 exerts opposite effects to CXCL10 on T helper cell cytokine production via CXCR3; CXCL4 (acting via CXCR3-B) downregulates IFN-γ and upregulates TH2 cytokines (IL-4, IL-5, IL-13), downregulates T-bet, upregulates GATA-3, and directly activates IL-5 and IL-13 promoters, whereas CXCL10 (acting via CXCR3-A) has opposite effects; anti-CXCR3 antibody blocks both. Antigen-specific T cell lines, quantitative RT-PCR, flow cytometry, ELISA, anti-CXCR3 neutralizing antibody, IL-5/IL-13 promoter-reporter assays The Journal of allergy and clinical immunology High 16337473

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact. Blood 546 11023497
2014 Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nature medicine 482 25326802
2013 Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. The New England journal of medicine 368 24350901
2008 Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. Journal of thrombosis and haemostasis : JTH 265 18489711
2012 Macrophage Phenotype Modulation by CXCL4 in Atherosclerosis. Frontiers in physiology 241 22275902
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