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Chemokine receptor CXCR3 agonist prevents human T-cell migration in a humanized model of arthritic inflammation

Lookup NU author(s): Dr Graeme O'Boyle, Christopher Fox, Dr Hannah Walden, Dr Joe Willet, Dr Emily Mavin, Dominic Hine, Dr Jeremy Palmer, Catriona Barker, Dr Chris Lamb, Professor Simi Ali, Professor John Kirby

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Abstract

The recruitment of T lymphocytes during diseases such as rheumatoid arthritis is regulated by stimulation of the chemokine receptors expressed by these cells. This study was designed to assess the potential of a CXCR3-specific small-molecule agonist to inhibit the migration of activated human T cells toward multiple chemokines. Further experiments defined the molecular mechanism for this anti-inflammatory activity. Analysis in vitro demonstrated agonist induced internalization of both CXCR3 and other chemokine receptors coexpressed by CXCR3+ T cells. Unlike chemokine receptor-specific antagonists, the CXCR3 agonist inhibited migration of activated T cells toward the chemokine mixture in synovial fluid from patients with active rheumatoid arthritis. A humanized mouse air-pouch model showed that intravenous treatment with the CXCR3 agonist prevented inflammatory migration of activated human T cells toward this synovial fluid. A potential mechanism for this action was defined by demonstration that the CXCR3 agonist induces receptor cross-phosphorylation within CXCR3-CCR5 heterodimers on the surface of activated T cells. This study shows that generalized chemokine receptor desensitization can be induced by specific stimulation of a single chemokine receptor on the surface of activated human T cells. A humanized mouse model was used to demonstrate that this receptor desensitization inhibits the inflammatory response that is normally produced by the chemokines present in synovial fluid from patients with active rheumatoid arthritis.


Publication metadata

Author(s): O'Boyle G, Fox CR, Walden HR, Willet JD, Mavin ER, Hine DW, Palmer JM, Barker CE, Lamb CA, Ali S, Kirby JA

Publication type: Article

Publication status: Published

Journal: Proceedings of the National Academy of Sciences

Year: 2012

Volume: 109

Issue: 12

Pages: 4598-4603

Print publication date: 20/03/2012

Date deposited: 02/01/2013

ISSN (print): 0027-8424

ISSN (electronic): 1091-6490

Publisher: National Academy of Sciences

URL: http://dx.doi.org/10.1073/pnas.1118104109

DOI: 10.1073/pnas.1118104109


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