@article{f74fbde8a70f494eb06a4bdea1939970,
title = "Targeting the chemokine network in atherosclerosis",
abstract = "Chemokines and their receptors represent a potential target for immunotherapy in chronic inflammation. They comprise a large family of cytokines with chemotactic activity, and their cognate receptors are expressed on all cells of the body. This network dictates leukocyte recruitment and activation, angiogenesis, cell proliferation and maturation. Dysregulation of chemokine and chemokine receptor expression as well as function participates in many pathologies including cancer, autoimmune diseases and chronic inflammation. In atherosclerosis, a lipiddriven chronic inflammation of middle-sized and large arteries, chemokines and their receptors participates in almost all stages of the disease from initiation of fatty streaks to mature atherosclerotic plaque formation. Atherosclerosis and its complications are the main driver of mortality and morbidity in cardiovascular diseases (CVD). Hence, exploring new fields of therapeutic targeting of atherosclerosis is of key importance. This review gives an overview of the recent advances on the role of key chemokines and chemokine receptors in atherosclerosis, addresses chemokine-based biomarkers at biochemical, imaging and genetic level in human studies, and highlights the clinial trials targeting atherosclerosis.",
keywords = "Chemokines, Chemokine receptors, Cardiovascular disease, Atherosclerosis, Biomarkers, Gene analysis, Mouse models, MONOCYTE CHEMOATTRACTANT PROTEIN-1, CORONARY-ARTERY-DISEASE, PROMOTES ATHEROSCLEROSIS, REDUCES ATHEROSCLEROSIS, CARDIOVASCULAR-DISEASE, LIMITS ATHEROSCLEROSIS, PLATELET ACTIVATION, CIRCULATING LEVELS, LESION DEVELOPMENT, PROGENITOR CELLS",
author = "Yi Yan and Manovriti Thakur and {van der Vorst}, {Emiel P. C.} and Christian Weber and Yvonne Doering",
note = "Funding Information: This study was supported by Deutsche Forschungsgemeinschaft ( DFG ); SFB1123, project A1 to Y.D. and C·W.; by the European Research Council ( ERC ) AdG °692,511 PROVASC to C·W., by the Swiss Heart Foundation project FF20099 to Y.D. and by a grant from the Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University and NWO- ZonMw Veni (91619053) to E.P·C.v.d.V. Funding Information: The chemokine receptor CXCR4 is a key regulator of cell homeostasis and seems to have atheroprotective functions. Recent studies showed that B-cell-specific knockout of CXCR4 in mice reduces bone marrow IgM production and plasma IgM levels, an effect which could be restored by the overexpression of CXCR4 [39,40]. Moreover, vascular CXCR4 suppresses atherosclerosis by sustaining endothelial barrier function through WNT/?-catenin signaling, and supporting a contractile SMC phenotype [41]. The longevity-associated variant (LAV) of the bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) has been found significantly enriched in long-living individual and its transfer was shown to limit atherosclerosis and skewed macrophages towards an M2-resolving phenotype through modulation of CXCR4 [42]. However, CXCR4/MIF interactions were described to mediate atherogenesis. The dual effect of CXCR4 has hampered the therapeutic application of CXCR4 agonist/antagonist in the treatment of atherosclerosis. Inspiringly, a soluble CXCR4 ectodomain mimics (msR4M-L1) was designed and has been proved to exhibite high affinity to MIF, with no binding to CXCL12. Fluorescence polarization and microscale thermophoresis in a binding-competition approach also confirmed an intact cardioprotective axis of MIF/CD74 in the presence of msR4M-L1. Next, the MIF/msR4M-L1 core binding region was mapped and the complex formation was verified using alanine mutants of both msR4M-L1 and MIF. The selective msR4M-L1/MIF binding was then specially blocked MIF/CXCR4-driven cell signaling response without any interference of CXCL12/CXCR4-elicited signaling in a yeast system that expresses human CXCR4. Moreover, HEK293-CD74 transfectant data showed that msR4M-L1did not affect the MIF binding to cell-surface CD74. In this study, msR4M-L1 dose-dependently inhibited MIF-triggered uptake of fluorescently labeled oxidized low-density lipoprotein and motility of human monocytes. Monocyte adhesion on human aortic endothelial was also inhibited by msR4M-L1 both under static condition and shear stress. In addition, msR4M-L1 localized to atherosclerotic plaques in a MIF-specific manner and inhibited MIF-mediated atherogenic leukocyte recruitment ex vivo. Apoe?/? mice receiving msR4M-L1 in parallel to HFD for 4.5 weeks exhibited reduced plaque burden, lesional macrophage accumulation and reduction of multiple inflammatory cytokines in the circulation [43]. Given the fact that chemokine ligand-receptor network promiscuity has been obstacle for chemokine ligands (receptors) as therapeutic targets in clinical application, the engineered chemokine-selective- GPCR-ectodomain-based mimicry principle that distinguishes disease-exacerbating from -protective signaling in this study would raise more attention to the chemokine-based strategy and could be of great potential for the treatment or prevention of other inflammatory diseases.This study was supported by Deutsche Forschungsgemeinschaft (DFG); SFB1123, project A1 to Y.D. and C?W.; by the European Research Council (ERC) AdG ?692,511 PROVASC to C?W., by the Swiss Heart Foundation project FF20099 to Y.D. and by a grant from the Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University and NWO-ZonMw Veni (91619053) to E.P?C.v.d.V. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = aug,
doi = "10.1016/j.atherosclerosis.2021.06.912",
language = "English",
volume = "330",
pages = "95--106",
journal = "Atherosclerosis",
issn = "0021-9150",
publisher = "Elsevier Ireland Ltd",
}