Glycosaminoglycan silencing by engineered CXCL12 variants

Gschwandtner, Martha; Trinker, Martin; Hecher, Bianca; Adage, Tiziana; Ali, Simi; Kungl, Andreas J.

doi:10.1016/j.febslet.2015.07.052

Cited by 9 publications

(13 citation statements)

References 55 publications

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“…Recently, inhibition of chemokine–GAG interaction has been explored as a complementary alternative for chemokine receptor antagonists. Both modified chemokines with enhanced GAG interaction and reduced activity on GPCRs, and aptamers that interfere with chemokine–GAG binding have entered clinical development (40, 41). The COOH-terminal CXCL9 domain CXCL9(74-103) potently bound GAGs, competed for GAG binding with several chemokines and was able to inhibit CXCL8- and MSU crystal-induced leukocyte migration to joints (42).…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that PA401, a CXCL8-based decoy protein, exerts strong anti-inflammatory activity in vivo (35–38). Also CCL2- and CXCL12-based decoy proteins with high GAG-binding affinity and reduced activity on GPCRs have been developed (39, 40). Interference with GAG interactions also forms the basis for the inhibition of lymphocyte migration with the spiegelmer NOX-A12 (41).…”

Section: Introductionmentioning

confidence: 99%

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CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions

et al. 2017

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Several acute and chronic inflammatory diseases are driven by accumulation of activated leukocytes due to enhanced chemokine expression. In addition to specific G protein-coupled receptor-dependent signaling, chemokine–glycosaminoglycan (GAG) interactions are important for chemokine activity in vivo. Therefore, the GAG–chemokine interaction has been explored as target for inhibition of chemokine activity. It was demonstrated that CXCL9(74-103) binds with high affinity to GAGs, competed with active chemokines for GAG binding and thereby inhibited CXCL8- and monosodium urate (MSU) crystal-induced neutrophil migration to joints. To evaluate the affinity and specificity of the COOH-terminal part of CXCL9 toward different GAGs in detail, we chemically synthesized several COOH-terminal CXCL9 peptides including the shorter CXCL9(74-93). Compared to CXCL9(74-103), CXCL9(74-93) showed equally high affinity for heparin and heparan sulfate (HS), but lower affinity for binding to chondroitin sulfate (CS) and cellular GAGs. Correspondingly, both peptides competed with equal efficiency for CXCL8 binding to heparin and HS but not to cellular GAGs. In addition, differences in anti-inflammatory activity between both peptides were detected in vivo. CXCL8-induced neutrophil migration to the peritoneal cavity and to the knee joint were inhibited with similar potency by intravenous or intraperitoneal injection of CXCL9(74-103) or CXCL9(74-93), but not by CXCL9(86-103). In contrast, neutrophil extravasation in the MSU crystal-induced gout model, in which multiple chemoattractants are induced, was not affected by CXCL9(74-93). This could be explained by (1) the lower affinity of CXCL9(74-93) for CS, the most abundant GAG in joints, and (2) by reduced competition with GAG binding of CXCL1, the most abundant ELR+ CXC chemokine in this gout model. Mechanistically we showed by intravital microscopy that fluorescent CXCL9(74-103) coats the vessel wall in vivo and that CXCL9(74-103) inhibits CXCL8-induced adhesion of neutrophils to the vessel wall in the murine cremaster muscle model. Thus, both affinity and specificity of chemokines and the peptides for different GAGs and the presence of specific GAGs in different tissues will determine whether competition can occur. In summary, both CXCL9 peptides inhibited neutrophil migration in vivo through interference with GAG interactions in several animal models. Shortening CXCL9(74-103) from the COOH-terminus limited its GAG-binding spectrum.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions

et al. 2017

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“…The effect of this mutant was assessed in an in vivo murine breast cancer seeding model. Treatment with the CXCL12α mutant inhibited migration of cancer cells, resulting in a decreased number of liver metastases (281).…”

Section: Dominant-negative Chemokine Mutantsmentioning

confidence: 99%

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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“…A variant of CXCL8 which has no ability to bind GPCRs but with increased GAG binding affinity inhibits trans-endothelial migration of neutrophils by displacing CXCL8 from the surface of endothelial cells [ 114 ]. A similar study by our group showed that a non-GPCR binding, increased-GAG binding CXCL12 variant showed a reduction in cell migration [ 115 ]. A CCL2 mutant with increased GAG binding was shown to displace multiple chemokines which could overcome the issues of redundancy [ 116 ], however high concentrations of chemokine may be required to occupy binding sites on all GAGs [ 43 , 117 ].…”

Section: Gags Nitration and Cxcl8 Functionmentioning

confidence: 98%

Regulation of Chemokine Function: The Roles of GAG-Binding and Post-Translational Nitration

Thompson

Martínez-Burgo

Sepuru

et al. 2017

IJMS

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The primary function of chemokines is to direct the migration of leukocytes to the site of injury during inflammation. The effects of chemokines are modulated by several means, including binding to G-protein coupled receptors (GPCRs), binding to glycosaminoglycans (GAGs), and through post-translational modifications (PTMs). GAGs, present on cell surfaces, bind chemokines released in response to injury. Chemokines bind leukocytes via their GPCRs, which directs migration and contributes to local inflammation. Studies have shown that GAGs or GAG-binding peptides can be used to interfere with chemokine binding and reduce leukocyte recruitment. Post-translational modifications of chemokines, such as nitration, which occurs due to the production of reactive species during oxidative stress, can also alter their biological activity. This review describes the regulation of chemokine function by GAG-binding ability and by post-translational nitration. These are both aspects of chemokine biology that could be targeted if the therapeutic potential of chemokines, like CXCL8, to modulate inflammation is to be realised.

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Glycosaminoglycan silencing by engineered CXCL12 variants

Cited by 9 publications

References 55 publications

CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions

CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions

Targeting Chemokine—Glycosaminoglycan Interactions to Inhibit Inflammation

Regulation of Chemokine Function: The Roles of GAG-Binding and Post-Translational Nitration

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