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Abstract
BackgroundExperimental autoimmune encephalomyelitis (EAE) is a model for inflammatory demyelinating diseases of the central nervous system (CNS), a group of autoimmune diseases characterized by inflammatory infiltration, demyelination, and axonal damage. miR-20a is dysregulated in patients with CNS inflammatory demyelinating diseases; however, the function of miR-20a remains unclear. In this study, we intended to explore the role of miR-20a in EAE.MethodsThe expression of miR-20a was detected by quantitative real-time PCR (qRT-PCR) in EAE mice and patients with MOG antibody-associated demyelinating diseases. CD4+ T cells of EAE mice were sorted, stimulated, and polarized with miR-20a knockdown. Activation and differentiation of CD4+ T cells were analyzed by flow cytometry. The expression of target gene Map3k9 was detected by qRT-PCR and western blot experiments. The binding of miR-20a to the 3’ UTR of Map3k9 was tested by luciferase assays. The feasibility of miR-20a as a therapeutic target to alleviate the severity of EAE was explored by intravenous administration of miR-20a antagomirs to EAE mice.ResultsmiR-20a was upregulated in splenocytes and lymph node cells, CD4+ T cells, and spinal cords of EAE mice. Moreover, miR-20a knockdown did not influence the activation of antigen-specific CD4+ T cells but promoted their differentiation into Treg cells. Map3k9 was predicted to be a target gene of miR-20a. The expressions of Map3k9 and miR-20a were negatively correlated, and miR-20a knockdown increased the expression of Map3k9. In addition, miR-20a binded to the 3’ UTR of Map3k9, and simultaneous knockdown of miR-20a and Map3k9 counteracted the enhanced differentiation of Tregs observed when miR-20a was knocked down alone. Furthermore, injection of miR-20a antagomirs to EAE mice reduced the severity of the disease and increased the proportion of Treg cells in peripheral immune organs.ConclusionsmiR-20a suppresses the differentiation of antigen-specific CD4+ T cells into Tregs in EAE by decreasing the expression of Map3k9. miR-20a antagomirs alleviate EAE, suggesting a new therapy for EAE and CNS inflammatory demyelinating diseases.
Highlights
Experimental autoimmune encephalomyelitis (EAE) is a model for inflammatory demyelinating diseases of the central nervous system (CNS), a group of autoimmune diseases characterized by inflammatory infiltration, demyelination, and axonal damage. miR-20a is dysregulated in patients with CNS inflammatory demyelinating diseases; the function of miR-20a remains unclear
Results miR‐20a is increased in EAE mice and patients with myelin oligodendrocyte glycoprotein (MOG) antibody‐associated demyelinating diseases To determine whether the miR-17-92 cluster is involved in the inflammatory response during EAE progression, we first tested the expression of the 6 miRNAs in the miR-17-92 cluster in splenocytes and lymph node cells
We detected the expression of miR-17, miR-18a, miR-20a, and miR-92a-1 in CD4+ T cells isolated from EAE and control mice, and miR-17 and miR-20a were found to be upregulated in EAE mice (Fig. 1B)
Summary
Experimental autoimmune encephalomyelitis (EAE) is a model for inflammatory demyelinating diseases of the central nervous system (CNS), a group of autoimmune diseases characterized by inflammatory infiltration, demyelination, and axonal damage. miR-20a is dysregulated in patients with CNS inflammatory demyelinating diseases; the function of miR-20a remains unclear. In the EAE model, IFN-γ-producing T helper (Th) and IL-17A-producing Th17 cells are considered crucial effector cells [9, 10, 15] They infiltrate into CNS lesions in both EAE mice and patients [9, 10], and transplanted autoreactive Th1 and Th17 cells can induce EAE symptoms in wildtype (WT) recipient mice. They activate astrocytes and microglia and secrete proinflammatory cytokines such as IFN-γ, IL-17A/F, and GM-CSF to cause tissue damage [5, 9, 10, 13, 14, 16,17,18]. Adoptive transfer of CD25+Foxp3+ regulatory T (Treg) cells is able to ameliorate EAE symptoms, whereas the depletion of Tregs worsens the disease [19], indicating the essential role of Tregs in the suppression of the autoimmune response and maintenance of immune tolerance
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