Background/Purpose:  Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease displaying a heavy female predominance during reproductive years. We have previously shown that toll-like receptor (TLR)7 and TLR8 are significantly up-regulated in peripheral blood mononuclear cells (PBMCs) of SLE patients and further induced with estrogen treatment. Conventionally, TLR7 and TLR8 binding to single-stranded RNA of viral origin to stimulate innate inflammatory responses, but recent studies have discovered that specific micro-RNA (miR) sequences can activate these receptors following packaging and secretion via extracellular vesicles (EVs). Our objective in this study was to explore the therapeutic potential of using a cocktail of miR antagonists to block TLR7 and TLR8 inflammatory pathways induced by EV-derived miRs in SLE.

Methods:  PBMCs were isolated from active SLE patients and adoptively transferred into immunodeficient NOD-scid IL-2rγ (null) mice to produce chimeras containing PBMCs from SLE patients using a similar protocol we have previously established for Sjöjren’s syndrome. Prior to transfer, PBMCs were treated with a cocktail of several locked nucleic acid miR antagonists or nonsense, scrambled RNA controls prior to injection. Blood was collected for both flow cytometry and cytokine analysis and tissues were processed for histopathological examination by H&E and immunohistochemistry.

Results:  Human T-cells (CD4+ and CD8+), B-cells, monocytes, and NK cells were all successfully recovered from whole blood of chimeric mice at similar levels in both treatment groups 21 days after adoptive transfer. However, inhibition with miR antagonists reduced levels of human IL-2, IL-6, IL-10, and TNF-α relative to scramble (control) treatment. While histopathological analysis revealed little to no inflammation in the skin and ear with either treatment, miR antogonists inhibited the robust responses detected with scramble RNA (control) treatment in the small intestine, liver, and kidney. Further characterization of infiltrates by immunohistochemistry confirmed the presence human CD3+ T-cells.

Conclusion:  These data establish a novel human-mouse model to study SLE and provide an experimental platform to further explore the therapeutic potential of suppressing EV-encapsulated miRs that trigger TLR7 and TLR8 signaling.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/targeting-micro-rnas-derived-from-extracellular-vesicles-to-inhibit-of-tlr7-and-tlr8-signaling-suppresses-inflammation-in-a-novel-human-mouse-chimeric-model-of-systemic-lupus-erythematosus/