MicroRNA 155-deficiency leads to decreased autoantibody levels and reduced severity of nephritis and pneumonitis in pristane-induced lupus

Abstract

ObjectiveWe herein examine the role of endogenous miR155 in the development of systemic manifestations in pristane induced lupus.Materials and methodsSystemic lupus in miR155-deficient and wild type mice was induced upon injection of pristane and analyzed after 8 months, PBS-injected mice served as controls. Glomerulonephritis and pneumonitis were quantified using the kidney biopsy score and a newly adapted histomorphometric image analysis system; lung tissue was further analyzed by tissue cytometry. Serum levels of anti-dsDNA, anti-histone and anti-chromatin antibodies were measured by ELISA. Frequencies of B cells, activated and regulatory CD4+ T cells as well as Th1, Th2, Th17 cells were measured by flow cytometry. RT-qPCR was used to measure expression levels of interferon-signature and T-cell subset related as well as miR155-associated genes.ResultsAfter induction of lupus, miR155-deficient mice had significant less pulmonary involvement (perivascular inflammatory area in mm2/mm2 lung area 0.00092±0.00015 vs. 0.0027±0.00075, p = 0.0347) and renal disease (glomerular activity score 1.95±0.19 vs 3±0.26, p = 0.0029) compared to wild types. MiR155-deficient mice had significantly lower serum levels of disease-associated auto-antibodies and decreased frequencies of activated CD4+CD25+ (Foxp3-) cells. Upon restimulation, CD4+ cells showed a less pronounced Th2 and Th17 and a slightly decreased Th1 response in mir155-deficient mice. Pristane-treated wild types showed significantly up-regulated expression of genes related to the INF-signature (MX1, IP10, IRF7, ISG15).ConclusionsMiR155-deficient mice had less severe organ involvement, lower serum auto-antibody levels, a less prominent T cell response and lower expressions of genes jointly responsible for disease development. Thus, antagonizing miR155 might be a future approach in treating SLE.

Altered levels of immune-regulatory microRNAs in plasma samples of patients with lupus nephritis

“…This assay may make fundamental changes in the management of the disease. 14 In accordance with the results of the present study, the miRNAs are likely to contribute to the pathogenesis and progression of LN and may be employed as diagnostic markers for LN.…”

“…These known microRNAs (miR-31, miR-125, 142-3p, miR-146, and miR-155) are important in the differentiation and development of immune responses as well as creating a malfunction in immune system responses. 14 - 18 Moreover, the association of the studied microRNAs with disease chronicity and activity index, and pathological findings were investigated in the patients with LN.…”

Non-Coding RNAs in CD4+ T Cells: New Insights Into the Pathogenesis of Systemic Lupus Erythematosus

“…Functionally, miR-155 targets CD62L to alter the phenotype of Treg cells in lupus-prone mice, suggesting that miR-155 is involved in the phenotypic heterogeneity of Treg cells. Deleting miR-155 limits the proportion of activated T cells and the levels of inflammatory cytokines IFN-γ, IL-4 and IL-17 secreted by Th1, Th2, and Th17 cells, thus alleviating the disease severity of lupus-prone mice (108). Diffuse alveolar hemorrhage (DAH) is a severe complication of SLE.…”

MicroRNA‐155 deficiency attenuates inflammation and oxidative stress in experimental autoimmune prostatitis in a TLR4‐dependent manner

“…13,32 Thus, WT mice, after the construc- WT mice. 34 Tang et al found that miR-155 −/− mice have reduced ischemia-reperfusion injury in the liver due to the inhibited expression of IL-17. 9 In addition, we found that in the EAP model, miR-155 −/− mice had a lower expression of TLR4 than WT mice, and it has already been reported that miR-155-KO mice were protected from chronic alcohol-induced increases in intestinal TNF-α and NF-κB activation.…”