Abstract
Systemic lupus erythematosus (SLE) patients exist an imbalance between regulatory T (Treg) and T helper 17 cells (Th17), which might be contributed by defective immune regulation of bone marrow derived mesenchymal stem cells (BM-MSCs) from SLE patients. Our microRNA array analysis showed markedly down-regulated expression levels of microRNA let-7f in BM-MSCs from SLE patients compared to those from normal controls (NOR). To explore the role of let-7f in the disease pathogenesis, we showed that expression levels of let-7f in SLE BM-MSCs were negatively associated with SLE disease activity, and the predicted let-7 family targeted gene expression of interlukin-6 (IL-6) was significantly higher in BM-MSCs from SLE patients compared to normal controls (NOR). Transient transfection of BM-MSCs with let-7f mimics or inhibitors showed reduced levels of let-7f impaired the proliferation rate of BM-MSCs, BM-MSC-mediated downregulation of Th17 cells and upregulation of Treg cells, increased the apoptosis rate of BM-MSCs through targeting IL-6 and activating signal transducers and activators of transcription-3 (STAT3) pathway, but had no significant effect on the differentiation of Th1 and Th2. Our findings showed a key role of let-7f in the imbalance of Treg/Th17 mediated by SLE BM-MSCs, suggesting the potential of manipulating let-7f expression in BM-MSCs for treating SLE patients.
Highlights
Accumulating evidences suggest that the imbalance of T-helper-cell (Th) subsets (Th1/Th2/T helper 17 cells (Th17)) and regulatory T-cells (Treg) contribute to the pathogenesis of systemic lupus erythematosus (SLE) [1,2,3], a systemic autoimmune disease characterized by disturbed T cell homeostasis
Levels of Let-7f expression negatively correlated with SLE disease activity index (SLEDAI, Figure 1A), 24 h urine proteinuria (Figure 1B) and erythrocyte sedimentation rate (ESR, Supplementary Table 4) significantly, supporting the potential involvement of let-7f in the pathogenesis of SLE, especially those with lupus nephritis. let-7f expression was only decreased in bone marrow derived mesenchymal stem cells (BM-Mesenchymal stem cells (MSCs)) from SLE patients with active disease, but not in BM-MSCs from inactive SLE patients and other connective tissue diseases (Figure 1C)
Our data showed that both mRNA (Figure 2B) and protein levels (Figure 2C) of IL-6 in SLE BM-MSCs were significantly elevated compared to those of healthy subjects, and IL-6 protein levels secreted by SLE BM-MSCs were negatively correlated with relative expression levels of let-7f in SLE BMMSCs (r = −0.71, p = 0.03)
Summary
Accumulating evidences suggest that the imbalance of T-helper-cell (Th) subsets (Th1/Th2/Th17) and regulatory T-cells (Treg) contribute to the pathogenesis of systemic lupus erythematosus (SLE) [1,2,3], a systemic autoimmune disease characterized by disturbed T cell homeostasis. This imbalance in T cell homeostasis is thought to be contributed by defective immune regulation of bone marrow derived mesenchymal stem cells (BM-MSCs) from SLE patients [4, 5], but the underlying mechanisms still largely unknown. The mechanisms for immune dysregulation of SLE BM-MSCs on Treg/Th17 cells are incompletely understood
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