MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis.
Mariola Kurowska-StolarskaStefano AliverniniEmma Garcia MelchorAziza ElmesmariBarbara TolussoClare TangeLuca PetriccaDerek S GilchristGabriele Di SanteChantal KeijzerLynn StewartClara Di MarioVicky MorrisonJames M BrewerDuncan PorterSimon W F MillingRonald D BaxterDavid McCareyElisa GremeseGreg LemkeGianfranco FerraccioliCharles McSharryIain B McInnesPublished in: Nature communications (2017)
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.
Keyphrases
- dendritic cells
- rheumatoid arthritis
- tyrosine kinase
- cell proliferation
- long non coding rna
- disease activity
- long noncoding rna
- regulatory t cells
- immune response
- epidermal growth factor receptor
- interstitial lung disease
- ankylosing spondylitis
- poor prognosis
- induced apoptosis
- transcription factor
- oxidative stress
- signaling pathway
- endoplasmic reticulum stress
- systemic sclerosis
- metabolic syndrome
- cell cycle arrest
- pi k akt
- peripheral blood
- genome wide
- copy number
- endothelial cells