Targeting Chemokine—Glycosaminoglycan Interactions to Inhibit Inflammation

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.

Expression levels of CXCR4 and CXCL12 in patients with rheumatoid arthritis and its correlation with disease activity

“…Previous studies have demonstrated that over the course of RA, inflammatory cells migrate from peripheral blood to synovial tissues and secrete a variety of inflammatory factors, resulting in the destruction of the synovial membrane (27,28). Chemokines serve an important role in the infiltration and migration of inflammatory cells (29). CXCL12 is the only chemokine that binds to the receptor CXCR4 (30).…”

Elucidating the Molecular Interactions of Chemokine CCL2 Orthologs with Flavonoid Baicalin

“… 64 Since it is widely accepted that the binding of chemokine–GAG interactions also regulates the functioning of chemokines during injurious conditions, few researchers have investigated the inhibition of the GAG–chemokine axis along with the receptor–chemokine axis as an alternative strategy. 65 On this line, various small chemokine binding proteins (CKBPs) from many parasites and viruses, 66 immunomodulatory proteins such as evasins, 67 , 68 chemokine mimetics such as mutated and truncated chemokines, 69 aptamers, 70 and other small-molecule compounds binding to chemokines/receptors 71 , 72 have been identified as potential blockers/inhibitors of the GPCR/GAG–chemokine axis. Alternatively, the natural plant products such as flavonoids have been used to treat various injurious ailments, and due to their low toxic nature and safe consumption, they have drawn remarkable attention in new alternative medicine.…”

Chemokines as Drivers of the Autoimmune Destruction in Type 1 Diabetes: Opportunity for Therapeutic Intervention in Consideration of an Optimal Treatment Schedule

“…Specific patterns of chemokines are often found in the serum of patients with autoimmune diseases, but also in those with acute or chronic inflammatory diseases. In order to lure leukocytes to the site of inflammation, many chemokines form a gradient along the endothelial layer by binding to glycosaminoglycans, like heparan sulfate (15). In response to the chemokine gradient migratory leukocytes start rolling along the endothelial layer with the help of selectins that interact with low-affinity (16).…”