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.
Kurowska-Stolarska, M., Alivernini, S., Melchor, E. G., 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., Mcinnes, I. B., MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis, <<NATURE COMMUNICATIONS>>, 2017; 8 (22): 15877-15891. [doi:10.1038/ncomms15877] [http://hdl.handle.net/10807/109601]
MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis
Alivernini, StefanoSecondo
;Tolusso, Barbara;Petricca, Luca;Di Sante, Gabriele;Di Mario, Clara;Gremese, Elisa;Ferraccioli, Gianfranco;
2017
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.
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