Chemokine CXCL4 interactions with extracellular matrix proteoglycans mediate widespread immune cell recruitment independent of chemokine receptors
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Dokumenter
- Fulltext
Forlagets udgivne version, 4,71 MB, PDF-dokument
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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 111930 |
| Tidsskrift | Cell Reports |
| Vol/bind | 42 |
| Udgave nummer | 1 |
| ISSN | 2211-1247 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
The authors would like to acknowledge numerous colleagues for reading and helping in drafting the manuscript. The Bioimaging Facility microscopes used in this study were purchased with grants from BBSRC , Wellcome Trust , and the University of Manchester Strategic Fund. Special thanks to Peter March, Roger Meadows, and Steven Marsden for their help with the microscopy. FRAP analyses was performed on a microscope within the Bioimaging Facilities at University of Leeds, supported by the Wellcome Trust ( WT104818MA ). Schematics have been drawn in BioRender. D.P.D. was supported by a Sir Henry Dale fellowship jointly funded by the Wellcome Trust and Royal Society (Grant Number 218570/Z/19/Z ) and a Wellcome Trust center grant (Grant Number 203128/A/16/Z ). R.L.M. was supported by The Carlsberg Foundation CF20-0412 . J.T. and R.L.M. were supported by The European Union’s Horizon 2020 Research and Innovation Program 899687 , HS-SEQ. R.L., M.S. and A.C. were supported by the Luxembourg Institute of Health (LIH), Luxembourg National Research Fund (INTER/FNRS grants 20/15084569 ), F.R.S.- FNRS-Télévie (grants 7.4529.19 , 7.8504.20 and 7.8508.22 ). R.L. is a Luxembourg National Research Fund PhD fellow ( PRIDE-14254520 “ I2TRON ”). T.M.H. was supported by NIH grants 1R01AI161880 and 1R01CA254402 .
Funding Information:
The authors would like to acknowledge numerous colleagues for reading and helping in drafting the manuscript. The Bioimaging Facility microscopes used in this study were purchased with grants from BBSRC, Wellcome Trust, and the University of Manchester Strategic Fund. Special thanks to Peter March, Roger Meadows, and Steven Marsden for their help with the microscopy. FRAP analyses was performed on a microscope within the Bioimaging Facilities at University of Leeds, supported by the Wellcome Trust (WT104818MA). Schematics have been drawn in BioRender. D.P.D. was supported by a Sir Henry Dale fellowship jointly funded by the Wellcome Trust and Royal Society (Grant Number 218570/Z/19/Z) and a Wellcome Trust center grant (Grant Number 203128/A/16/Z). R.L.M. was supported by The Carlsberg Foundation CF20-0412. J.T. and R.L.M. were supported by The European Union's Horizon 2020 Research and Innovation Program 899687, HS-SEQ. R.L. M.S. and A.C. were supported by the Luxembourg Institute of Health (LIH), Luxembourg National Research Fund (INTER/FNRS grants 20/15084569), F.R.S.-FNRS-Télévie (grants 7.4529.19, 7.8504.20 and 7.8508.22). R.L. is a Luxembourg National Research Fund PhD fellow (PRIDE-14254520 “I2TRON”). T.M.H. was supported by NIH grants 1R01AI161880 and 1R01CA254402. Conceptualization: A.L.G. R.L.M. and D.P.D. Methodology: A.L.G. R.K. A.R.E.R. A.J.L.R. N.P. B.K. C.H. L.M.R. H.L.B. C.L.S. E.A.Y. R.P.R. J.E.T. T.M.H. G.J.G. T.A.J. I.S. R.P.R. D.P.D. R.L. M.S. A.C. and I.M. Investigation: A.L.G. R.K. A.R.E.R. A.J.L.R. N.P. B.K. C.H. L.M.R. H.L.B. C.L.S. E.A.Y. R.P.R. T.A.J. I.S. D.P.D. R.L. M.S. A.C. and I.M. Funding acquisition: R.L.M. J.E.T. and D.P.D. Project administration: D.P.D. Supervision: T.M.H. G.J.G. R.P.R. R.L.M. and D.P.D. Writing – original draft: R.L.M. D.P.D. The authors declare no competing interests.
Publisher Copyright:
© 2022 The Authors
Antal downloads er baseret på statistik fra Google Scholar og www.ku.dk
ID: 333481030