Research ArticleGPCR SIGNALING

Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation

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Sci. Signal.  06 Nov 2018:
Vol. 11, Issue 555, eaaq1075
DOI: 10.1126/scisignal.aaq1075

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Biased chemokine responses

Like many other G protein–coupled receptors (GPCRs), chemokine receptors exhibit so-called biased agonism, whereby different ligands can stimulate either G protein– or β-arrestin–dependent signaling. Smith et al. investigated biased signaling by the receptor CXCR3, which directs T cell migration to sites of inflammation. The authors found that topical application of a small-molecule agonist that was β-arrestin biased, but not one that was G protein biased, exacerbated inflammation in a mouse model of contact hypersensitivity. The β-arrestin–biased agonist was more potent at stimulating mouse and human T cell chemotaxis in vitro and activated the kinase Akt, which promoted migration. Together, these data suggest that biased agonists of CXCR3, and perhaps other chemokine receptors, result in different physiological outcomes.

Abstract

The chemokine receptor CXCR3 plays a central role in inflammation by mediating effector/memory T cell migration in various diseases; however, drugs targeting CXCR3 and other chemokine receptors are largely ineffective in treating inflammation. Chemokines, the endogenous peptide ligands of chemokine receptors, can exhibit so-called biased agonism by selectively activating either G protein– or β-arrestin–mediated signaling after receptor binding. Biased agonists might be used as more targeted therapeutics to differentially regulate physiological responses, such as immune cell migration. To test whether CXCR3-mediated physiological responses could be segregated by G protein– and β-arrestin–mediated signaling, we identified and characterized small-molecule biased agonists of the receptor. In a mouse model of T cell–mediated allergic contact hypersensitivity (CHS), topical application of a β-arrestin–biased, but not a G protein–biased, agonist potentiated inflammation. T cell recruitment was increased by the β-arrestin–biased agonist, and biopsies of patients with allergic CHS demonstrated coexpression of CXCR3 and β-arrestin in T cells. In mouse and human T cells, the β-arrestin–biased agonist was the most efficient at stimulating chemotaxis. Analysis of phosphorylated proteins in human lymphocytes showed that β-arrestin–biased signaling activated the kinase Akt, which promoted T cell migration. This study demonstrates that biased agonists of CXCR3 produce distinct physiological effects, suggesting discrete roles for different endogenous CXCR3 ligands and providing evidence that biased signaling can affect the clinical utility of drugs targeting CXCR3 and other chemokine receptors.

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