FIGURE 6.

Summary of pathological role of CXCR7 and potential benefit of CXCR7 antagonism during ALI/ARDS. (A) CXCR7 functions predominantly as a scavenger receptor for its two ligands: the interferon-inducible chemokine CXCL11 and the constitutive chemokine CXCL12. Binding of its ligands leads to internalization of the CXCR7–ligand complex and ligand degradation. CXCL11 and CXCL12 also bind and activate the signaling chemokine receptors CXCR3 and CXCR4, respectively. The CXCR3/CXCR4/CXCR7 axes play an important role in lung inflammation. CXCR7 scavenging activity tightly regulates the extracellular levels of its ligands, facilitating the establishment and maintenance of CXCL11/12 chemokine concentration gradients and CXCR3⁺/CXCR4⁺ cell migration from the blood to the inflamed lung. In addition, increased CXCR7 expression in the inflamed lung has been reported to be associated with breathing pattern alteration and endothelial barrier dysfunction. (B) CXCR7 antagonism with the CXCR7 antagonist ACT-1004-1239 exhibits immunomodulatory effects: by blocking the scavenging activity of the receptor and consequently increasing CXCL11 and CXCL12 plasma concentrations, chemokine gradients are disrupted, inhibiting CXCR3⁺ and CXCR4⁺ cell migration to the inflamed lung. In addition, treatment with ACT-1004-1239, by increasing plasma CXCL12 and/or by direct inhibition of CXCR7 signaling, ameliorates ALI-induced breathing pattern alteration and endothelial barrier dysfunction.