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

Publication ,  Journal Article
Smith, JS; Nicholson, LT; Suwanpradid, J; Glenn, RA; Knape, NM; Alagesan, P; Gundry, JN; Wehrman, TS; Atwater, AR; Gunn, MD; MacLeod, AS; Rajagopal, S
Published in: Sci Signal
November 6, 2018

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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Published In

Sci Signal

DOI

EISSN

1937-9145

Publication Date

November 6, 2018

Volume

11

Issue

555

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Young Adult
  • T-Lymphocytes
  • Skin
  • Signal Transduction
  • Receptors, CXCR3
  • RNA, Small Interfering
  • Phosphorylation
  • Mice, Inbred C57BL
  • Mice
 

Citation

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Smith, J. S., Nicholson, L. T., Suwanpradid, J., Glenn, R. A., Knape, N. M., Alagesan, P., … Rajagopal, S. (2018). Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation. Sci Signal, 11(555). https://doi.org/10.1126/scisignal.aaq1075
Smith, Jeffrey S., Lowell T. Nicholson, Jutamas Suwanpradid, Rachel A. Glenn, Nicole M. Knape, Priya Alagesan, Jaimee N. Gundry, et al. “Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation.Sci Signal 11, no. 555 (November 6, 2018). https://doi.org/10.1126/scisignal.aaq1075.
Smith JS, Nicholson LT, Suwanpradid J, Glenn RA, Knape NM, Alagesan P, et al. Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation. Sci Signal. 2018 Nov 6;11(555).
Smith, Jeffrey S., et al. “Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation.Sci Signal, vol. 11, no. 555, Nov. 2018. Pubmed, doi:10.1126/scisignal.aaq1075.
Smith JS, Nicholson LT, Suwanpradid J, Glenn RA, Knape NM, Alagesan P, Gundry JN, Wehrman TS, Atwater AR, Gunn MD, MacLeod AS, Rajagopal S. Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation. Sci Signal. 2018 Nov 6;11(555).

Published In

Sci Signal

DOI

EISSN

1937-9145

Publication Date

November 6, 2018

Volume

11

Issue

555

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Young Adult
  • T-Lymphocytes
  • Skin
  • Signal Transduction
  • Receptors, CXCR3
  • RNA, Small Interfering
  • Phosphorylation
  • Mice, Inbred C57BL
  • Mice