MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis

Kurowska-Stolarska, M. et al. (2017) MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis. Nature Communications, 8, 15877. (doi: 10.1038/ncomms15877) (PMID:28639625) (PMCID:PMC5489689)

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Current treatments for rheumatoid arthritis (RA) do not reverse underlying aberrant immune function. A genetic predisposition to RA, such as HLA-DR4 positivity, indicates that dendritic cells (DC) are of crucial importance to pathogenesis by activating auto-reactive lymphocytes. Here we show that microRNA-34a provides homoeostatic control of CD1c+ DC activation via regulation of tyrosine kinase receptor AXL, an important inhibitory DC auto-regulator. This pathway is aberrant in CD1c+ DCs from patients with RA, with upregulation of miR-34a and lower levels of AXL compared to DC from healthy donors. Production of pro-inflammatory cytokines is reduced by ex vivo gene-silencing of miR-34a. miR-34a-deficient mice are resistant to collagen-induced arthritis and interaction of DCs and T cells from these mice are reduced and do not support the development of Th17 cells in vivo. Our findings therefore show that miR-34a is an epigenetic regulator of DC function that may contribute to RA.

Item Type:Articles
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Elmesmari, Dr Aziza and Brewer, Professor James and Milling, Professor Simon and Gilchrist, Dr Derek and Keijzer, Dr Chantal and Morrison, Dr Vicky and Baxter, Dr Ronald and Tange, Miss Clare and Kurowska-Stolarska, Professor Mariola and Porter, Dr Duncan and Garcia Melchor, Dr Emma and Stewart, Ms Lynn and McCarey, Dr David and McSharry, Dr Charles and Alivernini, Mr Stefano
Authors: Kurowska-Stolarska, M., Alivernini, S., Garcia Melchor, E., Elmesmari, A., Tolusso, B., Tange, C., Petricca, L., Gilchrist, D. S., Di Sante, G., Keijzer, C., Stewart, L., Di Mario, C., Morrison, V., Brewer, J. M., Porter, D., Milling, S., Baxter, R. D., McCarey, D., Gremese, E., Lemke, G., Ferraccioli, G., McSharry, C., and McInnes, I. B.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
College of Science and Engineering > School of Chemistry
Journal Name:Nature Communications
Publisher:Nature Research
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Nature Communications 8:15877
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
514111MicroRNA in monocytes: its contribution to the pathogenesis of arthritis and cardiovascular co-morbidityMariola Kurowska-StolarskaArthritis Research UK (ARC)19213III -IMMUNOLOGY
690421Glasgow Molecular Pathology (GMP) NodeKarin OienMedical Research Council (MRC)MR/N005813/1ICS - EXPERIMENTAL THERAPEUTICS