Cell Reports (Jan 2023)
Chemokine CXCL4 interactions with extracellular matrix proteoglycans mediate widespread immune cell recruitment independent of chemokine receptors
- Anna L. Gray,
- Richard Karlsson,
- Abigail R.E. Roberts,
- Amanda J.L. Ridley,
- Nabina Pun,
- Bakhtbilland Khan,
- Craig Lawless,
- Rafael Luís,
- Martyna Szpakowska,
- Andy Chevigné,
- Catherine E. Hughes,
- Laura Medina-Ruiz,
- Holly L. Birchenough,
- Iashia Z. Mulholland,
- Catherina L. Salanga,
- Edwin A. Yates,
- Jeremy E. Turnbull,
- Tracy M. Handel,
- Gerard J. Graham,
- Thomas A. Jowitt,
- Ingo Schiessl,
- Ralf P. Richter,
- Rebecca L. Miller,
- Douglas P. Dyer
Affiliations
- Anna L. Gray
- Wellcome 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 Karlsson
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark
- Abigail R.E. Roberts
- University 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. Ridley
- Wellcome 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 Pun
- Wellcome 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 Khan
- Wellcome 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 Lawless
- Wellcome 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 Luís
- Immuno-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 Szpakowska
- Immuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health, 4354 Esch-sur-Alzette, Luxembourg
- Andy Chevigné
- Immuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health, 4354 Esch-sur-Alzette, Luxembourg
- Catherine E. Hughes
- Chemokine Research Group, School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK
- Laura Medina-Ruiz
- Chemokine Research Group, School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK
- Holly L. Birchenough
- Wellcome 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. Mulholland
- Wellcome 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. Salanga
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA
- Edwin A. Yates
- Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK
- Jeremy E. Turnbull
- Copenhagen 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. Handel
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA
- Gerard J. Graham
- Chemokine Research Group, School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK
- Thomas A. Jowitt
- Wellcome 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 Schiessl
- Geoffrey 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. Richter
- University 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. Miller
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark
- Douglas P. Dyer
- Wellcome 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; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 1
p. 111930
Abstract
Summary: 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.
