Background The inflammatory Ly-6Chigh monocyte subset is essential in innate immunity but it also contributes to the pathogenesis of many inflammatory and autoimmune disorders. Strategies to manipulate this cell subset are thus of therapeutic importance. The pre-B-cell colony enhancing factor (PBEF/visfatin/Nampt) is an essential enzyme in the NAD biosynthetic pathway that also exerts a key role in the persistence of inflammation through the induction of the expression of the TNF-α and IL-6 pro-inflammatory cytokines. PBEF is highly expressed in the serum of patients with a variety of inflammatory disorders, including rheumatoid arthritis.
Objectives The present study aimed at evaluating the therapeutic potential of delivering anti-inflammatory siRNA to Ly6Chigh monocytes for immuno-intervention in arthritis.
Methods Using the collagen-induced arthritis mouse model, we show that the delivery of a short interfering (si)RNA against PBEF into the Ly-6Chigh monocytes is able to reduce molecular and cellular markers of inflammation, both systemically and locally, thereby inhibiting disease progression. Upon intravenous injection, siRNA localize to circulating Ly-6Chigh monocytes, but not to Ly-6Clow monocytes. Efficient silencing of PBEF in Ly-6Chigh monocytes reduces the downstream TNF-α and IL-6 production and lead to decreased number of infiltrating leukocytes in arthritic joints and to reduced number of splenic pathogenic T cells. Importantly, when the siRNA-containing liposome formulation is tailored for translation to the clinic and tested on human peripheral blood mononuclear cells, inhibition of PBEF and its downstream mediators in CD14+CD16- monocytes reduces the generation of Th17 cells.
Conclusions Overall, our preclinical results demonstrate the feasibility and utility of targeting disease-causing genes with RNAi technology in Ly-6Chigh monocytes for therapeutic intervention in arthritis.
Disclosure of Interest None Declared
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