Background and aims We have previously demonstrated that toll-like receptor (TLR)7 and TLR8 are significantly up-regulated in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) patients and can be further induced with oestrogen treatment. It has recently been shown that specific micro-RNA (miR) sequences packaged in extracellular vesicles can stimulate these receptors in addition to the conventional activation by binding single-stranded RNA of viral origin. The aim of this study was to explore the feasibility of using miR antagonists to block TLR7 and TLR8-mediated inflammatory pathways.
Methods Human-mouse chimaeras were generated by adoptively transferring PBMCs from active SLE patients into immunodeficient NOD-scid IL-2rγ (null) mice using a modified protocol that we previously established in Sjöjren’s syndrome. Prior to transfer, SLE patient PBMCs were treated either with a cocktail of locked nucleic acid antagonists targeting several miRs or nonsense, scrambled controls. At 21 days post-transfer, blood was collected for flow cytometry and cytokine analysis; tissues were processed for histopathological examination by H and E and immunohistochemistry.
Results The phenotypic characteristics of various immune cells were similar in both experimental groups; however, inhibition with miR antagonists reduced levels of human IL-2, IL-6, IL-10, and TNF-α relative to scramble (control) treatment. Histopathological analysis revealed that miR antogonists inhibited the robust responses detected with control treatment in the small intestine, liver, and kidney. Further characterisation of infiltrates confirmed the presence human CD3+ T-cells.
Conclusions These data establish a novel model to study SLE and provide experimental evidence that TLR7 and TLR8 targeted miR antagonists have therapeutic potential in SLE.
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