Abstract
Leukocyte migration into tissues depends on the activity of chemokines that form concentration gradients to guide leukocytes to a specific site. Interaction of chemokines with their specific G protein-coupled receptors (GPCRs) on leukocytes induces leukocyte adhesion to the endothelial cells, followed by extravasation of the leukocytes and subsequent directed migration along the chemotactic gradient. Interaction of chemokines with glycosaminoglycans (GAGs) is crucial for extravasation in vivo. Chemokines need to interact with GAGs on endothelial cells and in the extracellular matrix in tissues in order to be presented on the endothelium of blood vessels and to create a concentration gradient. Local chemokine retention establishes a chemokine gradient and prevents diffusion and degradation. During the last two decades, research aiming at reducing chemokine activity mainly focused on the identification of inhibitors of the interaction between chemokines and their cognate GPCRs. This approach only resulted in limited success. However, an alternative strategy, targeting chemokine-GAG interactions, may be a promising approach to inhibit chemokine activity and inflammation. On this line, proteins derived from viruses and parasites that bind chemokines or GAGs may have the potential to interfere with chemokine-GAG interactions. Alternatively, chemokine mimetics, including truncated chemokines and mutant chemokines, can compete with chemokines for binding to GAGs. Such truncated or mutated chemokines are characterized by a strong binding affinity for GAGs and abrogated binding to their chemokine receptors. Finally, Spiegelmers that mask the GAG-binding site on chemokines, thereby preventing chemokine-GAG interactions, were developed. In this review, the importance of GAGs for chemokine activity in vivo and strategies that could be employed to target chemokine-GAG interactions will be discussed in the context of inflammation.
Highlights
Chemotactic cytokines or chemokines, complement fragments C3a and C5a, bioactive lipids such as leukotrienes, and formylated peptides interact with specific G protein-coupled receptors (GPCRs) on leukocytes and are predominant mediators of leukocyte migration to an inflammatory site [1]
The function of chemokines is not restricted to leukocyte physiology alone, since they contribute to several processes such as tumor growth and metastasis, haematopoiesis, angiogenesis, and organogenesis [3, 5, 11]
Evidence is accumulating that the chemokine-GAG interaction may be an interesting target for the inhibition of inflammation
Summary
Chemotactic cytokines or chemokines, complement fragments C3a and C5a, bioactive lipids such as leukotrienes, and formylated peptides interact with specific G protein-coupled receptors (GPCRs) on leukocytes and are predominant mediators of leukocyte migration to an inflammatory site [1]. Inhibition of this interaction compromised both directional guidance and restriction of neutrophil motility This suggests that leukocytes, once in the tissue, can migrate to the site of inflammation through the gradient of local GAG-bound chemokines. Endothelial HS has an important function during inflammation: acting as a ligand for L-selectin during neutrophil rolling, playing a role in chemokine transcytosis and being responsible for the binding and presentation of chemokines at the luminal surface of the endothelium. KSPGs formed a chemokine gradient to mediate infiltration of neutrophils to the cornea through interaction with CXCL1, indicating the importance of these PG/CXCL1 complexes in the inflammatory response in eye inflammation [112, 113]. Stability of CXCL1 homodimer, formation of chemokine gradient for cellular trafficking, neutrophil migration in the lung Binding to CXCR2 and neutrophil migration in vivo Gradient formation in inflammatory response in the eye GAG/CXCL2/CXCR2 complex formation Stability of CXCL2 homodimer Neutrophil migration in the lung Neutrophil migration in vivo in response to CXCL2 High affinity binding Prevention of degradation Heterodimer formation in vivo High affinity binding Heterodimer formation in vivo High affinity binding CXCL8-induced formation of reactive oxygen species and in vitro chemotaxis of neutrophils Inhibition of elastase release High affinity binding Neutrophil activity in vivo, inhibition of elastase release from neutrophils In vivo neutrophil migration, transcytosis Oligomerization Protection from CD26/DPPIV activity Recruitment of plasmacytoid cells Recruitment and transendothelial migration of T cells High affinity binding Oligomerization Recruitment of plasmacytoid cells Anti-proliferative effect on endothelial cells Anti-fibrotic effect in lungs Antiviral effect against Dengue virus Recruitment and transendothelial migration of T cells Cell migration in vivo High affinity binding High affinity binding Recruitment of plasmacytoid cells Recruitment and transendothelial migration of T cells High affinity binding Oligomerization Protection from CD26/DPPIV activity T cell activation in rheumatoid arthritis synovium Intraperitoneal leukocyte accumulation and angiogenesis Anti-HIV activity High affinity binding
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