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

Mariola Kurowska-Stolarska (), Stefano Alivernini, Emma Garcia Melchor, Aziza Elmesmari, Barbara Tolusso, Clare Tange, Luca Petricca, Derek S. Gilchrist, Gabriele Di Sante, Chantal Keijzer, Lynn Stewart, Clara Di Mario, Vicky Morrison, James M. Brewer, Duncan Porter, Simon Milling, Ronald D. Baxter, David McCarey, Elisa Gremese, Greg Lemke, Gianfranco Ferraccioli, Charles McSharry and Iain B. McInnes ()
Additional contact information
Mariola Kurowska-Stolarska: Institute of Infection, Immunity and Inflammation, University of Glasgow
Stefano Alivernini: Fondazione Policlinico Universitario A. Gemelli, Catholic University of the Sacred Heart
Emma Garcia Melchor: Institute of Infection, Immunity and Inflammation, University of Glasgow
Aziza Elmesmari: Institute of Infection, Immunity and Inflammation, University of Glasgow
Barbara Tolusso: Fondazione Policlinico Universitario A. Gemelli, Catholic University of the Sacred Heart
Clare Tange: Institute of Infection, Immunity and Inflammation, University of Glasgow
Luca Petricca: Fondazione Policlinico Universitario A. Gemelli, Catholic University of the Sacred Heart
Derek S. Gilchrist: Institute of Infection, Immunity and Inflammation, University of Glasgow
Gabriele Di Sante: Fondazione Policlinico Universitario A. Gemelli, Catholic University of the Sacred Heart
Chantal Keijzer: Institute of Infection, Immunity and Inflammation, University of Glasgow
Lynn Stewart: Institute of Infection, Immunity and Inflammation, University of Glasgow
Clara Di Mario: Fondazione Policlinico Universitario A. Gemelli, Catholic University of the Sacred Heart
Vicky Morrison: Institute of Infection, Immunity and Inflammation, University of Glasgow
James M. Brewer: Institute of Infection, Immunity and Inflammation, University of Glasgow
Duncan Porter: Institute of Infection, Immunity and Inflammation, University of Glasgow
Simon Milling: Institute of Infection, Immunity and Inflammation, University of Glasgow
Ronald D. Baxter: Institute of Infection, Immunity and Inflammation, University of Glasgow
David McCarey: NHS Greater Glasgow and Clyde
Elisa Gremese: Fondazione Policlinico Universitario A. Gemelli, Catholic University of the Sacred Heart
Greg Lemke: Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies
Gianfranco Ferraccioli: Fondazione Policlinico Universitario A. Gemelli, Catholic University of the Sacred Heart
Charles McSharry: Institute of Infection, Immunity and Inflammation, University of Glasgow
Iain B. McInnes: Institute of Infection, Immunity and Inflammation, University of Glasgow

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms15877

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