Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms15877
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Funding
- Arthritis Research UK (ARUK) Career Development Fellowship [x19213]
- Novo Nordisk UK
- Oliver Bird Rheumatism Programme/Nuffield Foundation
- European League Against Rheumatism (EULAR)
- Catalonian Society of Rheumatology
- ARUK Fellowship [x20848]
- ARUK Centre of Excellence for the Pathogenesis of Rheumatoid Arthritis [RACE/x20298]
- MRC [MR/N005813/1] Funding Source: UKRI
- Medical Research Council [MR/N005813/1] Funding Source: researchfish
- Versus Arthritis [20848, 19213] Funding Source: researchfish
- Versus Arthritis
- Cancer Research UK [20816] Funding Source: researchfish
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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.
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