Glycosaminoglycan Interactions with Chemokines Add Complexity to a Complex System

This study investigates if treatment with a peptide corresponding to the 30 C-terminal amino acids of CXCL9, CXCL9(74-103), ameliorates joint inflammation in a murine model of antigen-induced arthritis (AIA). AIA was induced in male C57BL/6J mice. Intravenous injection of CXCL9(74-103), simultaneously performed with a tibiofemoral challenge with methylated BSA (mBSA) as antigen in mice immunized with mBSA, diminished the accumulation of leukocytes, in particular neutrophils, in the synovial cavity. The levels of the chemokines CXCL1, CXCL2, and CXCL6 and of the cytokine IL-6 were decreased in inflamed periarticular tissue of mice treated with the CXCL9-derived peptide compared to non-treated AIA mice. In addition, CXCL9(74-103) treatment substantially reduced joint and cartilage damage. CXCL9(74-103) competes with CXCL6 and CCL3 for binding to the glycosaminoglycans heparan sulfate and chondroitin sulfate in vitro. In vivo, CXCL9(74-103) quickly binds to blood vessels in joints as observed by confocal microscopy. Next, we evaluated if later treatment with CXCL9(74-103) had a beneficial impact on joint inflammation. CXCL9(74-103) injection 6 h after mBSA challenge still reduced neutrophil accumulation in the joint, although it did not reduce chemokine and IL-6 concentrations. However, a delay of treatment until 12 h after challenge had no effect on cell recruitment and chemokine and IL-6 levels. Taken together, we demonstrated that treatment with a peptide, which interferes with the interaction between chemokines and glycosaminoglycans, from the beginning of the disease controlled the massive accumulation of neutrophils in the joint of AIA mice, greatly impacting on joint inflammation and tissue damage.

Section: Discussionmentioning

confidence: 99%

The chemokine fragment CXCL9(74–103) diminishes neutrophil recruitment and joint inflammation in antigen-induced arthritis

Boff

Crijns

Janssens

et al. 2018

“…Chemokine function is precisely regulated, as tightly regulated transcriptional expression of ligands and receptors constitutes a versatile system, and after secretion, the chemokines can be proteolytically processed and/or suffer other posttranslational modifications . Binding of certain chemokines to glycosaminoglycans, although they are not required for receptor activation in vitro, also contributes to the complexity of chemokine biology . The presence of non‐signaling receptors that act as decoys also regulates chemokine levels and modulate their responses …”

Section: Chemokines: Key Players For Cell Migrationmentioning

confidence: 99%

Remodeling our concept of chemokine receptor function: From monomers to oligomers

Martínez-Muñoz

Villares

Rodrı́guez-Fernández

et al. 2018

The chemokines direct leukocyte recruitment in both homeostatic and inflammatory conditions, and are therefore critical for immune reactions. By binding to members of the class A G protein-coupled receptors, the chemokines play an essential role in numerous physiological and pathological processes. In the last quarter century, the field has accumulated much information regarding the implications of these molecules in different immune processes, as well as mechanistic insight into the signaling events activated through their binding to their receptors. Here, we will focus on chemokine receptors and how new methodological approaches have underscored the role of their conformations in chemokine functions. Advances in biophysical-based techniques show that chemokines and their receptors act in very complex networks and therefore should not be considered isolated entities. In this regard, the chemokine receptors can form homo- and heterodimers as well as oligomers at the cell surface. These findings are changing our view as to how chemokines influence cell biology, identify partners that regulate chemokine function, and open new avenues for therapeutic intervention.

“…Binding and retention of chemokines on cell surfaces or the extracellular matrix is critical for the formation of locally confined chemotactic gradients . However, the interactions of chemokines with GAGs is not uniform and can fine‐tune the function of chemokines . CXCL12α possesses one GAG binding site in its first β‐strand and differs therein from CXCL12β and particularly CXCL12γ, which harbor additional GAG binding sites at their extended C‐termini …”

Section: Introductionmentioning

confidence: 99%

Characterization of a chimeric chemokine as a specific ligand for ACKR3

Ameti

Melgrati

Radice

et al. 2018

and CXCL11 bind to the canonical receptors CXCR4 and CXCR3, respectively. Here, we present the engineering of a chemokine-like chimera, which selectively binds to ACKR3. The addition of a ybbR13 tag at the C-terminus allows site specific enzymatic labeling with a plethora of fluorescent dyes. The chimera is composed of the N-terminus of CXCL11 and the main body and C-terminus of CXCL12 and selectively interacts with ACKR3 with high affinity, while not interfering with binding of CXCL11 and CXCL12 to their cognate receptors. We further provide evidence that the chimera can be used to study ACKR3 function in vivo.