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.
Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
Cell Rep. 2023 Jan 31;42(1):111930. doi: 10.1016/j.celrep.2022.111930. Epub 2023 Jan 5.
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.
白细胞从血管向组织中的募集是免疫系统的关键组成部分，但也是炎症性疾病的关键。趋化因子在这个过程中起着核心作用，但由于缺乏对其机制的理解，在炎症期间尚未成为治疗靶点。具体来说，CXCL4（血小板因子 4，PF4）没有确定的受体来解释其功能。在这里，我们使用生物物理、体外和体内技术来确定 CXCL4 介导的白细胞募集的机制。我们证明，CXCL4 与内皮细胞外基质中蛋白聚糖上的糖胺聚糖 (GAG) 结合，导致白细胞与血管的粘附增加、血管通透性增加以及一系列白细胞的非特异性募集。此外，GAG 硫酸化赋予了趋化因子定位的选择性。这些发现为趋化因子生物学提供了机制上的见解，并为未来的治疗靶点提供了依据。
