Chemokine Cooperativity Is Caused by Competitive Glycosaminoglycan Binding

Verkaar, Folkert; Offenbeek, Jody van; Lee, Miranda M.C. van der; Lith, Lambertus H. C. J. van; Watts, Anne O.; Rops, Angelique L.; Aguilar, David C.; Ziarek, Joshua J.; Vlag, Johan van der; Handel, Tracy M.; Volkman, Brian F.; Proudfoot, Amanda E. I.; Vischer, Henry F.; Zaman, Guido J.R.; Smit, Martine J.

doi:10.4049/jimmunol.1302159

Cited by 32 publications

(36 citation statements)

References 46 publications

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“…Both CCL21 and CCL19 bound to a hexasaccharide as observed by SPR analysis (220). GAG binding also plays an essential role in chemokine cooperativity (221). In the absence of cooperative chemokines, CCL19 and CCL21 bound to CCR7 or GAGs on the endothelial cell surface.…”

Section: Consequences Of Ccl19 and Ccl21 Binding To Glycosaminoglycansmentioning

confidence: 87%

Targeting Chemokine—Glycosaminoglycan Interactions to Inhibit Inflammation

2020

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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.

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Section: Consequences Of Ccl19 and Ccl21 Binding To Glycosaminoglycansmentioning

confidence: 87%

Targeting Chemokine—Glycosaminoglycan Interactions to Inhibit Inflammation

2020

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“…Recently, Verkar et al demonstrated that chemokine cooperativity is not strictly dependent on the receptor of the cooperative chemokine, but can originate from chemokine heterodimerization or from their binding to membrane-tethered glycosaminoglycans (GAGs), which establishes a chemokine concentration gradient(42). In this respect, the CCR2 ligands CCL2, binds to several GAGs with relatively high affinity(37–41).…”

Section: Discussionmentioning

confidence: 99%

Role of the C-C chemokine receptor-2 in a murine model of injury-induced osteoarthritis

Longobardi

Temple

Tagliafierro

et al. 2017

Osteoarthritis and Cartilage

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Objective We previously found in our embryonic studies that proper regulation of the chemokine CCL12 through its sole receptor CCR2, is critical for joint and growth plate development. In the present study, we examined the role of CCR2 in injury-induced-osteoarthritis (OA). Method We used a murine model of injury-induced-OA (destabilization of medial meniscus, DMM), and systemically blocked CCR2 using a specific antagonist (RS504393) at different times during disease progression. We examined joint degeneration by assessing cartilage (cartilage loss, chondrocyte hypertrophy, MMP-13 expression) and bone lesions (bone sclerosis, osteophytes formation) with or without the CCR2 antagonist. We also performed pain behavioral studies by assessing the weight distribution between the normal and arthritic hind paws using the IITS incapacitance meter. Results Testing early vs. delayed administration of the CCR2 antagonist demonstrated differential effects on joint damage. We found that OA changes in articular cartilage and bone were ameliorated by pharmacological CCR2 blockade, if given early in OA development: specifically, pharmacological targeting of CCR2 during the first 4 weeks following injury, reduced OA cartilage and bone damage, with less effectiveness with later treatments. Importantly, our pain-related behavioral studies showed that blockade of CCR2 signaling during early, 1–4wks post-surgery or moderate, 4–8wks post-surgery, OA was sufficient to decrease pain measures, with sustained improvement at later stages, after treatment was stopped. Conclusions Our data highlight the potential efficacy of antagonizing CCR2 at early stages to slow the progression of post-injury OA and, in addition, improve pain symptoms.

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“…It has recently been suggested that the phenomenon of chemokine cooperativity, in which one chemokine can enhance the activity of a second, is due to competition for matrix GAGs, rather than downstream signaling pathway convergence or heterodimerization (Verkaar et al, 2014).…”

Section: Heparin and Cytokines Growth Factors Selectins And Promentioning

confidence: 99%