ArticleCell reports2023
Chemokine CXCL4 interactions with extracellular matrix proteoglycans mediate widespread immune cell recruitment independent of chemokine receptors.
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Article in Cell reports, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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42 citing papers in PubMed, 71 citations in OpenAlex.
- Airway macrophage specific glycocalyx expression and remodeling following viral infection.Matrix biology : journal of the International Society for Matrix Biology · 2026Article
- Identification of an Immune Cell Gene Signature for Predicting Response and Prognosis in Rectal Cancer Patients Undergoing Neoadjuvant Chemoradiotherapy.Cancer medicine · 2026Article
- Immunomodulatory role of megakaryocytes in the hematopoietic niche of myeloproliferative neoplasms.Haematologica · 2026Article
- Platelet-derived biomaterials in osteoporosis: mechanisms, evidence and translational prospects.Journal of biological engineering · 2026Review
- Tetrameric assembly disruption impairs CXCL4 chaperon ability for DNA and type I interferon immune amplification.Communications biology · 2026Article
- The extracellular matrix in inflammation and cancer.Molecular biomedicine · 2026Review
- Beyond Structure: The Dynamic Role of the Extracellular Matrix Components in Immune Evasion.Cancer communications (London, England) · 2026Review
- Interferon receptor gene dosage differentially regulates hypoxia-induced platelet activation and pulmonary hypertension in down syndrome.Frontiers in immunology · 2026Article
- Glycosaminoglycans and Their Role in Capillary Walls.Advances in experimental medicine and biology · 2026Review
- Quorum sensing geneFrontiers in microbiology · 2026Article
- Thrombocytopenia in murine schistosomiasis is associated with platelet uptake by liver macrophages that have a distinct activation phenotype.PLoS pathogens · 2025Article
- Rules of engagement: Determinants of chemokine receptor activation and selectivity by CCL27 and CCL28.The Journal of biological chemistry · 2025Article
- Emerging Roles of Megakaryocytes in Immune Regulation and Potential Therapeutic Prospects.Cells · 2025Review
- Platelet factor 4 and stromal cell-derived factor are novel prognostic biomarkers for cerebral vasospasm and mortality after subarachnoid hemorrhage.Scientific reports · 2025Article
- Endothelial cell activation enhances thromboinflammation in vaccine-induced immune thrombotic thrombocytopenia.Blood advances · 2025Article
- Proteomic and lipidomic analysis of low-density lipoprotein identifies potential biomarkers of early estrogen receptor-positive breast cancer.Cancer & metabolism · 2025Article
- Nbeal2 knockout mice are not protected against hypoxia-induced pulmonary vascular remodeling and pulmonary hypertension.Blood advances · 2025Article
- The Role of CXCL4 in Systemic Sclerosis: DAMP, Auto-Antigen and Biomarker.International journal of molecular sciences · 2025Review
- Extracellular matrix and pregnancy: functions and opportunities caught in the net.Reproductive biology and endocrinology : RB&E · 2025Review
- The multifaceted role of XCL1 in health and disease.Protein science : a publication of the Protein Society · 2025Review
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Authors and funding
24 authors at 8 institutions in 4 countries.
Anna L GrayWellcome Centre for Cell-Matrix Research, Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance NHS Group, University of Manchester, Manchester, UK.
Richard KarlssonCopenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
Abigail R E RobertsUniversity of Leeds, School of Biomedical Sciences, Faculty of Biological Sciences, School of Physics and Astronomy, Faculty of Engineering and Physical Sciences, Astbury Centre for Structural Molecular Biology, and Bragg Centre for Materials Research, Leeds LS2 9JT, UK.
Amanda J L RidleyWellcome Centre for Cell-Matrix Research, Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
Nabina PunWellcome Centre for Cell-Matrix Research, Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
Bakhtbilland KhanWellcome Centre for Cell-Matrix Research, Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
Craig LawlessWellcome Centre for Cell-Matrix Research, Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
Rafael LuísImmuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health, 4354 Esch-sur-Alzette, Luxembourg; Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg; Tumor Immunotherapy and Microenvironment, Department of Cancer Research, Luxembourg Institute of Health, 2012 Luxembourg, Luxembourg.
Martyna SzpakowskaImmuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health, 4354 Esch-sur-Alzette, Luxembourg.
Andy ChevignéImmuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health, 4354 Esch-sur-Alzette, Luxembourg.
Catherine E HughesChemokine Research Group, School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.
Laura Medina-RuizChemokine Research Group, School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.
Holly L BirchenoughWellcome Centre for Cell-Matrix Research, Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
Iashia Z MulhollandWellcome Centre for Cell-Matrix Research, Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
Catherina L SalangaSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Edwin A YatesDepartment of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
Jeremy E TurnbullCopenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark; Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK; Centre for Glycosciences, Keele University, Keele, Staffordshire ST5 5BG, UK.
Tracy M HandelSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Gerard J GrahamChemokine Research Group, School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.
Thomas A JowittWellcome Centre for Cell-Matrix Research, Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
Ingo SchiesslGeoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance NHS Group, University of Manchester, Manchester, UK; Division of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Ralf P RichterUniversity of Leeds, School of Biomedical Sciences, Faculty of Biological Sciences, School of Physics and Astronomy, Faculty of Engineering and Physical Sciences, Astbury Centre for Structural Molecular Biology, and Bragg Centre for Materials Research, Leeds LS2 9JT, UK.
Rebecca L MillerCopenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
Douglas P DyerWellcome Centre for Cell-Matrix Research, Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance NHS Group, University of Manchester, Manchester, UK. Electronic address: douglas.dyer@manchester.ac.uk.
Manchester Academic Health Science Centre · GBUniversity of Copenhagen · DKUniversity of Glasgow · GBLuxembourg Institute of Health · LUUniversity of California San Diego · USUniversity of Leeds · GBUniversity of Liverpool · GBUniversity of Luxembourg · LU
Funding
It's a tug of war: structure, consequences, and inhibition of CXCR4 and ACKR3 responses to lymphocyte chemoattractant CXCL12R01AI161880 · NIAID · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI HANDEL, TRACY M, KUFAREVA, IRINA · 2021 to 2025
$3.4MRegulation of the metastasis promoting chemokine receptor ACKR3 by GPCR kinases, Gβγ and arrestinsR01CA254402 · NCI · PURDUE UNIVERSITY · PI HANDEL, TRACY M, TESMER, JOHN · 2020 to 2024
$3.2MSignaling circuits that drive cell movement and ligand scavenging by chemokine receptor CCR2R01GM136202 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI HANDEL, TRACY M, KUFAREVA, IRINA · 2020 to 2023
$1.9MNCI NIH HHS R01 CA254402NIAID NIH HHS R01 AI161880NIGMS NIH HHS R01 GM136202Wellcome TrustWellcome Trust 203128/A/16/ZWellcome Trust 218570/Z/19/ZWellcome Trust WT104818MA
Abstract
Leukocyte recruitment from the vasculature into tissues is a crucial component of the immune system but is also key to inflammatory disease. Chemokines are central to this process but have yet to be therapeutically targeted during inflammation due to a lack of mechanistic understanding. Specifically, CXCL4 (Platelet Factor 4, PF4) has no established receptor that explains its function. Here, we use biophysical, in vitro, and in vivo techniques to determine the mechanism underlying CXCL4-mediated leukocyte recruitment. We demonstrate that CXCL4 binds to glycosaminoglycan (GAG) sugars on proteoglycans within the endothelial extracellular matrix, resulting in increased adhesion of leukocytes to the vasculature, increased vascular permeability, and non-specific recruitment of a range of leukocytes. Furthermore, GAG sulfation confers selectivity onto chemokine localization. These findings present mechanistic insights into chemokine biology and provide future therapeutic targets.
Indexed as
Platelet Factor 4ProteoglycansChemokinesExtracellular MatrixGlycosaminoglycansReceptors, ChemokineChemokinesGlycosaminoglycansPlatelet Factor 4ProteoglycansReceptors, ChemokinechemokineCP: ImmunologyCXCL4extracellular matrixglycosaminoglycanleukocytePF4proteoglycanrecruitmenttrafficking
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