miR-155 Deficiency Ameliorates Autoimmune Inflammation of Systemic Lupus Erythematosus by Targeting S1pr1 in Faslpr/lpr Mice

Abstract

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 Faslpr/lpr (miR-155−/−Faslpr/lpr) mice were obtained by crossing miR-155−/− and Faslpr/lpr mice. Clinical SLE features such as glomerulonephritis, autoantibody levels, and immune system cell populations were compared between miR-155−/−Faslpr/lpr and Faslpr/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−/−Faslpr/lpr mice showed milder SLE clinical features than did Faslpr/lprmice. As compared with Faslpr/lpr mice, miR-155−/−Faslpr/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−/−Faslpr/lpr than Faslpr/lpr mice; the CD4+/CD8+ T cell ratio was restored in miR-155−/−Faslpr/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 Faslpr/lpr mice. miR-155−/−Faslpr/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.

MicroRNAs in the key events of systemic lupus erythematosus pathogenesis

“…in experiments, mice deficient in mir-146a (miR146a −/− ) respond hypersensitively to lipopolysaccharide (lps) stimulation and produce large numbers of interleukins (il), such as il-6, il-1β, il-10 and tumour necrosis factor (TNF)-α, and moreover, during aging develop an autoimmune disorder characterized as tissue damage by multiorgan lymphocytic and monocytic infiltrates and formation of anti-dsdNa autoantibodies 87 . interestingly, Xing et al demonstrated in a recent study of mir-155 knockdown lupus-prone Fas lpr/lpr mouse models a milder sle phenotype than in wild-type strains 88 . cells of the innate immune system are equipped with several families of pattern recognition receptors (prrs) to recognized molecules derived from pathogens or damaged cells.…”

“…T FH cells are characterized by the transcription factor B cell lymphoma-6 (Bcl-6) and secretion of il-21 and are supposed to interfere with sle pathogenesis. sle model mice depleted of mir-155, mirNa-155 -/-Fas lpr/lpr develop a phenotype with a reduced proportion of spleen T FH and subsequent lower levels of igG and igm titres 88 . similarly, reduced levels of Bcl-6 and il-21 in mouse spleens and lower levels of il-21 in the mouse serum are found in this model 88 .…”

“…sle model mice depleted of mir-155, mirNa-155 -/-Fas lpr/lpr develop a phenotype with a reduced proportion of spleen T FH and subsequent lower levels of igG and igm titres 88 . similarly, reduced levels of Bcl-6 and il-21 in mouse spleens and lower levels of il-21 in the mouse serum are found in this model 88 . recently, two mirNas, cluster mir-17-92 and mir-10a, were described as modulators of T FH genesis, Bcl-6 expression in particular (ref.…”

“…mirs are molecules with the potential to serve as markers of the disease as well as a future therapeutic option. sle mouse models with knockdown mir-155 exhibit a milder disease with smaller amounts of igG antibodies 88 . Whereas mir-155 is one of the fully occupied mirs in innate as well as adaptive immune responses, further studies to exclude infection, malignancies and other adverse effects following inhibition of mir-155 in vivo are intensively required.…”

Immunopathogenesis of systemic lupus erythematosus and rheumatoid arthritis: the role of aberrant expression of non-coding RNAs in T cells

“…Finally, the miRNA cluster miR-17-92 appeared to be critical for Tfh cell differentiation and function [43,44]. Several members of the miR-17-92 cluster, including miR-17, miR-17a, mice were found to be resistant to the development of SLE lesions by the regulation of a target gene S1pr1 of miR-155 [47]. Therefore, the decreased miR-155 in SLE T cells could play a negative feedback loop to control STAT-3 phosphorylation and IL-21 production.…”