Liposomal AntagomiR‐155‐5p Restores Anti‐Inflammatory Macrophages and Improves Arthritis in Preclinical Models of Rheumatoid Arthritis

Abstract

IntroductionWe previously reported an increased expression of miR‐155 in rheumatoid arthritis (RA) patients blood monocytes that could be responsible for impaired monocyte polarization to anti‐inflammatory M2‐like macrophages. In this study, we employed two pre‐clinical models of RA: the Collagen‐Induce‐Arthritis (CIA) and the K/BxN Serum‐Transfer‐Arthritis (STA), to examine the therapeutic potential of antagomiR‐155‐5p entrapped within PEGylated (PEG)‐liposomes in resolution of arthritis and re‐polarization of monocytes towards anti‐inflammatory M2 phenotype.MethodsAntagomiR‐155‐5p or antagomiR‐control were encapsulated in PEG‐liposomes of 100 nm in size and ‐10mV in zeta potential with high antagomiR loading efficiency (above 80%). Mice were injected intravenously with 1,5nmol/100μL PEG‐liposomes containing antagomiR‐155‐5p or control after induction of arthritis.ResultsWe demonstrated the biodistribution of fluorescently tagged‐PEG‐liposomes to inflamed joints 1 hour after injection of fluorescently tagged‐PEG‐liposomes and as well as their subsequent liver's accumulation after 48 hours, indicative of hepatic clearance, in arthritic mice. Injection of PEG‐liposomes containing antagomiR‐155‐5p decreased arthritis score and paw swelling as compared to PEG‐liposomes containing antagomiR‐control or systemic delivery of free antagomiR‐155‐5p. Moreover, treatment with PEG‐liposomes containing antagomiR‐155‐5p lead to the restoration of bone marrow monocytes defect in anti‐inflammatory macrophage differentiation without any significant functional change in other immune cells including splenic B and T cells.ConclusionThe injection of antagomiR‐155‐5p encapsulated in PEG‐liposomes allows delivering small RNA to monocytes/macrophages, reduced joint inflammation in murine models of RA, providing a promising strategy in human disease.image

SOCS1 is a critical checkpoint in immune homeostasis, inflammation and tumor immunity

“…These studies highlight the potential of enhancing SOCS1 levels and/or developing drugs that mimic SOCS1 activity in the treatment of autoimmune disease. Alternative approaches to increase SOCS1 levels, such as antagomirs that target miR-155, may also have some utility given the recent advances in RNA delivery systems ( 181 ).…”

Macrophage plasticity: signaling pathways, tissue repair, and regeneration

“…For example, inhibition of miR‐155 has been shown to attenuate M1 polarization and promote M2‐like phenotypes in models of inflammatory diseases, such as rheumatoid arthritis and. 221 , 222 Conversely, overexpression of miR‐21 or miR‐124 has been investigated to promote M2 polarization and resolve inflammation in conditions such as sepsis and spinal cord injury. 223 …”