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.

中文翻译：

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靶向趋化因子-糖胺聚糖相互作用来抑制炎症。

白细胞迁移到组织中取决于趋化因子的活性，趋化因子形成浓度梯度以将白细胞引导至特定部位。趋化因子与其在白细胞上的特异性G蛋白偶联受体（GPCR）的相互作用诱导白细胞粘附于内皮细胞，随后白细胞外渗并随后沿趋化梯度定向迁移。趋化因子与糖胺聚糖（GAG）的相互作用对于体内外渗至关重要。趋化因子需要与内皮细胞和组织中细胞外基质中的GAG相互作用，以使其出现在血管内皮上并产生浓度梯度。局部趋化因子保留建立了趋化因子梯度，并防止了扩散和降解。在过去的二十年中 旨在降低趋化因子活性的研究主要集中于鉴定趋化因子与其同源GPCR之间相互作用的抑制剂。这种方法仅导致有限的成功。但是，针对趋化因子-GAG相互作用的另一种策略可能是抑制趋化因子活性和炎症的一种有前途的方法。在这条线上，结合趋化因子或GAG的病毒和寄生虫衍生的蛋白质可能会干扰趋化因子-GAG的相互作用。或者，趋化因子模拟物，包括截短的趋化因子和突变型趋化因子，可与趋化因子竞争结合GAG。这样的截短或突变的趋化因子的特征在于对GAG的强结合亲和力和与它们的趋化因子受体的结合被消除。最后，已开发出可掩盖趋化因子上GAG结合位点从而阻止趋化因子与GAG相互作用的镜像异构体。在这篇综述中，将在炎症的背景下讨论GAG对于体内趋化因子活性的重要性以及可用于靶向趋化因子-GAG相互作用的策略。