MiR-155 deficiency ameliorates autoimmune inflammation of systemic lupus erythematosus by targeting S1pr1 in Fas^lpr/lpr mice

MicroRNA-155 (miR-155) was previously found involved in the development of systemic lupus erythematosus (SLE) and other autoimmune diseases and the inflammatory response; however, the detailed mechanism of miR-155 in SLE is not fully understood. To explore the in vivo role of miR-155 in the pathogenesis of SLE, miR-155-deficient Fas^lpr/lpr (miR-155^-/-Fas^lpr/lpr) mice were obtained by crossing miR-155^-/- and Fas^lpr/lpr mice. Clinical SLE features such as glomerulonephritis, autoantibody levels, and immune system cell populations were compared between miR-155^-/-Fas^lpr/lpr and Fas^lpr/lpr mice. Microarray analysis, RT-PCR, Western blot, and luciferase reporter gene assay were used to identify the target gene of miR-155. miR-155^-/-Fas^lpr/lpr mice showed milder SLE clinical features than did Fas^lpr/lprmice. As compared with Fas^lpr/lpr mice, miR-155^-/-Fas^lpr/lpr mice showed less deposition of total IgA, IgM, and IgG and less infiltration of inflammatory cells in the kidney. Moreover, the serum levels of IL-4 and IL-17a, secreted by Th2 and Th17 cells, were lower in miR-155^-/-Fas^lpr/lpr than Fas^lpr/lpr mice; the CD4+/CD8+ T cell ratio was restored in miR-155^-/-Fas^lpr/lpr mice as well. Sphingosine-1-phosphate receptor 1 (S1PR1) was found as a new target gene of miR- 155 by in vitro and in vivo studies; its expression was decreased in SLE patients and Fas^lpr/lpr mice. miR-155^-/-Fas^lpr/lpr mice are resistant to the development of SLE by the regulation of the target gene S1pr1. miR-155 might be a new target for therapeutic intervention in SLE.