MicroRNA-146 and cell trauma down-regulate expression of the psoriasis-associated atypical chemokine receptor ACKR2

Shams, K., Kurowska-Stolarska, M. , Schütte, F., Burden, A. D., McKimmie, C. S. and Graham, G. J. (2018) MicroRNA-146 and cell trauma down-regulate expression of the psoriasis-associated atypical chemokine receptor ACKR2. Journal of Biological Chemistry, 293(8), pp. 3003-3012. (doi: 10.1074/jbc.M117.809780) (PMID:29279330) (PMCID:PMC5827444)

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Chemokines are the principal regulators of leukocyte migration and are essential for initiation and maintenance of inflammation. Atypical chemokine receptor 2 (ACKR2) binds and scavenges proinflammatory CC-chemokines, regulates cutaneous T-cell positioning, and limits the spread of inflammation in vivo. Altered ACKR2 function has been implicated in several inflammatory disorders, including psoriasis, a common and debilitating T cell-driven disorder characterized by thick erythematous skin plaques. ACKR2 expression is abnormal in psoriatic skin, with decreased expression correlating with recruitment of T cells into the epidermis and increased inflammation. However, the molecular mechanisms that govern ACKR2 expression are not known. Here, we identified specific psoriasis-associated microRNAs (miRs) that bind ACKR2, inhibit its expression, and are active in primary cultures of human cutaneous cells. Using both in silico and in vitro approaches, we show that miR-146b and miR-10b directly bind the ACKR2 3'-UTR and reduce expression of ACKR2 transcript and protein in keratinocytes and lymphatic endothelial cells, respectively. Moreover, we demonstrate that ACKR2 expression is further downregulated upon cell trauma, an important trigger for the development of new plaques in many psoriasis patients (the Koebner phenomenon). We found that tensile cell stress leads to rapid ACKR2 downregulation and concurrent miR-146b upregulation. Together, we provide, for the first time, evidence for epigenetic regulation of an atypical chemokine receptor. We propose a mechanism by which cell trauma and miRs coordinately exacerbate inflammation via downregulation of ACKR2 expression and provide a putative mechanistic explanation for the Koebner phenomenon in psoriasis.

Item Type:Articles
Keywords:Chemokine, immunology, inflammation, microRNA (miRNA), psoriasis.
Glasgow Author(s) Enlighten ID:Shams, Dr Kave and Burden, Professor David and Schuette, Dr Fabian and Kurowska-Stolarska, Professor Mariola and McKimmie, Dr Clive and Graham, Professor Gerard
Authors: Shams, K., Kurowska-Stolarska, M., Schütte, F., Burden, A. D., McKimmie, C. S., and Graham, G. J.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN (Online):1083-351X
Published Online:26 December 2017
Copyright Holders:Copyright © 2018 The American Society for Biochemistry and Molecular Biology, Inc.
First Published:First published in Journal of Biological Chemistry 293(8): 3003-3012
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
600961Dissecting the chemokine basis for the orchestration of the in vivo inflammatory responseGerard GrahamWellcome Trust (WELLCOTR)099251/Z/12/ZIII -IMMUNOLOGY