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

Kurowska-Stolarska1 M, Alivernini S, Melchor EG, Elmesmari A, Tolusso B, et al.

Nat Commun.2017 Jun 22; 8:15877.

Speaker: Yu-Ting Lo (羅愈婷)                              Time: 15:00~16:00, Oct 11, 2017

Commentator: Dr. Hsiao-Sheng Liu (劉校生老師) Place: Room 601

Abstract:

     Rheumatoid arthritis (RA) is the most common autoimmune polyarthritis associated with breach of tolerance to self-proteins Dendritic cells (DC) play a role in the initiation of RA by stimulating auto-reactive T and B cells, which thereafter orchestrate progression to chronic joint inflammation and destruction The majority of current RA treatments target inflammation, but do not promote tolerance. Therefore, restoring homeostatic DC function to achieve tolerance would be a compelling strategy for treatment of RA. RA synovial fluid contains conventional CD1c+ and inflammatory CD1c+ cells that are critical for Th17 responses and support synovial inflammation by producing TNF upon TLR7/8 stimulation. Accordingly, the authors sought to dissect molecular pathways that drive the activation of RA CD1c+ DCs. Herein they showed that CD1c+ DCs from RA patients had greater miR-34a expression and lower levels of tyrosine kinase receptor AXL compared to which from healthy donors. Production of pro-inflammatory cytokines was reduced by inhibition of miR-34a in RA CD1c+ DCs. MiR-34a-deficient mice were resistant to collagen-induced arthritis. At last, they proved that miR-34a provided homeostatic control of CD1c+ DC activation via regulation of AXL, an important inhibitory DC auto-regulator. In conclusion, this aberrant homeostatic control of DC activation in CD1c+ DCs from RA patients, with upregulation of miR-34a and downregulation of AXL, may contribute to RA. Thus, modulating the miR-34a/AXL pathway in RA DCs by using miR-34a inhibitors or AXL agonist could be a feasible therapeutic strategy to restore homoeostasis and promote resolution of RA.

References:

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2.      McInnes, I. B. & Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365, 2205–2219 (2011).