Spread of psoriasiform inflammation to remote tissues is restricted by the atypical chemokine receptor ACKR2

Graham, G. et al. (2017) Spread of psoriasiform inflammation to remote tissues is restricted by the atypical chemokine receptor ACKR2. Journal of Investigative Dermatology, 137(1), pp. 85-94. (doi: 10.1016/j.jid.2016.07.039) (PMID:27568525) (PMCID:PMC5176004)

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Elucidating the poorly defined mechanisms by which inflammatory lesions are spatially restricted in vivo, is of critical importance in understanding skin disease. Chemokines are the principal regulators of leukocyte migration and are essential in the initiation and maintenance of inflammation. The membrane-bound psoriasis associated atypical chemokine receptor ACKR2 binds, internalises and degrades most pro-inflammatory CC-chemokines. Here we investigate the role of ACKR2 in limiting the spread of cutaneous psoriasiform inflammation to sites that are remote from the primary lesion. Circulating factors capable of regulating ACKR2 function at remote sites were identified and examined using a combination of clinical samples, relevant primary human cell cultures, in vitro migration assays and the imiquimod-induced model of psoriasiform skin inflammation. Localised inflammation and IFNγ together upregulate ACKR2 in remote tissues, protecting them from the spread of inflammation. ACKR2 controls inflammatory T-cell chemotaxis and positioning within the skin, preventing an epidermal influx that is associated with lesion development. Our results have important implications for our understanding of how spatial restriction is imposed on the spread of inflammatory lesions, and highlight systemic ACKR2 induction as a therapeutic strategy in the treatment and prevention of psoriasis and potentially a broad range of other immune-mediated diseases.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Wilson, Dr Gillian and Shams, Dr Kave and Burden, Professor David and Singh, Mr Mark and McKimmie, Dr Clive and Holmes, Dr Susan and Graham, Professor Gerard
Authors: Graham, G., Shams, K., Wilson, G., Singh, M., van den Bogaard, E., Brocq, M. L., Holmes, S., Schalkwijk, J., Burden, D. A., McKimmie, C. S., and Graham, G. J.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Journal of Investigative Dermatology
ISSN (Online):1523-1747
Published Online:26 August 2016
Copyright Holders:Copyright © 2016 Elsevier
First Published:First published in Journal of Investigative Dermatology 137(1):85-94
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
681091The ACKR2-CCR2 axis in development and diseaseGerard GrahamMedical Research Council (MRC)MR/M019764/1III -IMMUNOLOGY
600961Dissecting the chemokine basis for the orchestration of the in vivo inflammatory responseGerard GrahamWellcome Trust (WELLCOME)099251/Z/12/ZIII -IMMUNOLOGY