Abstract
The inflammatory chemokines CXCL9, CXCL10, and CXCL11 are predominantly induced by interferon (IFN)-γ and share an exclusive chemokine receptor named CXC chemokine receptor 3 (CXCR3). With a prototype function of directing temporal and spatial migration of activated T cells and natural killer cells, and inhibitory effects on angiogenesis, these CXCR3 ligands have been implicated in infection, acute inflammation, autoinflammation and autoimmunity, as well as in cancer. Intense former research efforts led to recent and ongoing clinical trials using CXCR3 and CXCR3 ligand targeting molecules. Scientific evidence has claimed mutual redundancy, ligand dominance, collaboration or even antagonism, depending on the (patho)physiological context. Most research on their in vivo activity, however, illustrates that CXCL9, CXCL10, and CXCL11 each contribute to the activation and trafficking of CXCR3 expressing cells in a non-redundant manner. When looking into detail, one can unravel a multistep machinery behind final CXCR3 ligand functions. Not only can specific cell types secrete individual CXCR3 interacting chemokines in response to certain stimuli, but also the receptor and glycosaminoglycan interactions, major associated intracellular pathways and susceptibility to processing by particular enzymes, among others, seem ligand-specific. Here, we overview major aspects of the molecular properties and regulatory mechanisms of IFN-induced CXCR3 ligands, and propose that their in vivo non-redundancy is a reflection of the unprecedented degree of versatility that seems inherent to the IFN-related CXCR3 chemokine system.
Highlights
The inflammatory chemokines CXCL9, CXCL10, and CXCL11 are predominantly induced by interferon (IFN)-γ and share an exclusive chemokine receptor named CXC chemokine receptor 3 (CXCR3)
We overview major aspects of the molecular properties and regulatory mechanisms of IFN-induced CXCR3 ligands, and propose that their in vivo non-redundancy is a reflection of the unprecedented degree of versatility that seems inherent to the IFN-related CXCR3 chemokine system
In addition to interaction with specific G protein-coupled receptor (GPCR), chemokine availability, activity and receptor preference is modulated at multiple levels including chemokine interactions with glycosaminoglycans (GAGs), atypical chemokine receptors (ACKRs), gene transcription, mRNA stability, alternative gene splicing, mutual synergism or antagonism, and posttranslational modifications [14,15,16,17]
Summary
Chemotactic cytokines or chemokines are low molecular mass proteins (± 8–12 kDa) with a hallmark function of directing leukocyte migration in a time- and site-dependent manner [1,2,3,4,5,6]. It was proposed that, during the course of immune responses, differential stimuli induce CXCL9, CXCL10, and CXCL11 expression by specific cell types, contributing to unique temporal and spatial expression of IFN-inducible CXCR3 ligands Their non-redundant biological roles in vivo are probably a consequence of multidimensional regulation of the specific activity of IFN-induced CXCR3 agonists as indicated by, for example, ligand-specific receptor- and GAG-binding features, major associated intracellular signaling pathways and differential susceptibility to enzymatic processing. Ensuing studies revealed that IP-10 and Mig are chemotactic cytokines or chemokines that lack a conserved ELR amino acid motif and contain two conserved Cys residues separated by one random residue (“X”) in their NH2-terminal sequences They both act on CXCR3, which was originally reported as a selective receptor for these two chemokines [29]. The IFN-inducible CXCR3 chemokines show circa 40% homology in their amino acid sequences and are produced by a variety of cells including human microvascular endothelial cells (HUMEC), keratinocytes and fibroblasts (Table 1; Figure 2)
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