A new therapeutic strategy for inhibiting pro-inflammatory macrophages in pre-clinical models of rheumatoid arthritis: using antagomir-155 encapsulated in pegylated liposomes

We found that an increased expression of miR-155 in monocytes/macrophages was responsible for the impaired differentiation of monocytes in anti-inflammatory macrophages. We have identified 7 microRNAs that differentiate monocytes of RA patients from those of healthy. Unfortunately, we could not confirm implication of new miR, except miR-155.  

Also, we demonstrated that miR-155-driven defect of anti-inflammatory macrophage differentiation was also present in 2 pre-clinical models of RA: serum-transfer-arthritis (STA) and collagen-induce-arthritis (CIA) mice. We validated the therapeutic strategy using antagomiR-155 encapsulated in PEG-liposomes for decreasing arthritis incidence and paw volume-size in CIA and STA. Moreover, PEG-liposomes were specific of monocytes and had no impact on other immune cells. Finally, we demonstrated a restoration of monocytes polarization in M2 macrophages in bone-marrow-derived-macrophages but also in mice synovial tissue.

Monocytes-macrophages are key players in the pathogenesis of Rheumatoid Arthritis (RA). An up-regulation of miR-155 expression has been shown in RA synovial macrophages, fibroblasts, peripheral blood and synovial fluid CD14+ monocytes. Our group has demonstrated epigenetic mechanism driving preferential differentiation of RA monocyte into pro-inflammatory macrophages published in The Journal of Immunology (Paoletti A et al J Immunol. 2019 Oct 1;203(7):1766-1775).  

We found that an increased expression of miR-155 in monocytes/macrophages was responsible for the impaired differentiation of monocytes in anti-inflammatory macrophages.  

We have identified 7 microRNAs, that differentiate monocytes of RA patients from those of healthy. Unfortunately, we could not confirm implication of new miR, except miR-155. Based on this and robust evidence of the pathogenic role of miR-155 in experimental and clinical arthritis, we proposed to test the therapeutic utility of targeting miR-155 in arthritis. 

This program research achieved 2 important goals: 

1- We demonstrated that miR-155-driven defect of anti-inflammatory macrophage differentiation was also present in 2 pre-clinical models of RA: serum-transfer-arthritis (STA) and collagen-induce-arthritis (CIA) mice 

2- We validated the therapeutic strategy using antagomiR-155 encapsulated in PEG-liposomes as compared to systemic delivery for decreasing arthritis incidence in CIA and STA mice. Moreover, PEG-liposomes were specific of monocytes and had no impact on other immune cells.  

Finally, injection of PEG-liposome containing antagomiR-155 with a small amount of antagomiR, we demonstrated a decrease of arthritis incidence, and a restoration of monocytes polarization in M2 macrophages in bone-marrow-derided-macrophages but also in mice synovial tissue. 

Overall, this research program contributed to a better understanding of the abnormalities of monocytes–macrophages in pathophysiology of RA. miR-155 inhibition is already in phase II in hematological malignancies with an apparent good safety profile. We confirm efficacy and specificity of antagomiR-155 encapsulated in PEG-liposomes in pre-clinical models of RA, with this approach specifically addressed to monocytes/macrophages could emerge as a novel and possible treatment for RA patients.