A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes

Serr, Isabelle; Scherm, Martin G.; Zahm, Adam M.; Schug, Jonathan; Flynn, Victoria K.; Hippich, Markus; Kälin, Stefanie; Becker, Maike; Achenbach, Peter; Nikolaev, Alexei; Gerlach, Katharina; Liebsch, Nicole; Loretz, Brigitta; Lehr, Claus Michael; Kirchner, Benedikt; Spornraft, Melanie; Haase, Bettina; Segars, James H.; Küper, Christoph; Palmisano, Ralf; Waisman, Ari; Willis, Richard A.; Kim, Wan‐Uk; Weigmann, Benno; Kaestner, Klaus H.; Ziegler, Anette G.; Daniel, Carolin

doi:10.1126/scitranslmed.aag1782

Cited by 49 publications

(72 citation statements)

References 54 publications

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“…2 evidence also highlighted the potential role of miRNAs in T1D. Serr et al 8 showed that miR-181a was up-regulated in CD4 + T cells from T1D patients and also that miR-181a/nuclear factor of activated T cells 5 regulated T cell function in the T1D patients. Serr et al 8 showed that miR-181a was up-regulated in CD4 + T cells from T1D patients and also that miR-181a/nuclear factor of activated T cells 5 regulated T cell function in the T1D patients.…”

Section: Introductionmentioning

confidence: 97%

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MiR‐885‐3p is down‐regulated in peripheral blood mononuclear cells from T1D patients and regulates the inflammatory response via targeting TLR4/NF‐κB signaling

Zhang

Wang

et al. 2019

The Journal of Gene Medicine

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Background: Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the progressive destruction of insulin-production pancreatic β cells. Recently, microRNAs (miRNAs) have emerged as important regulators in T1D. The present study aimed to determine miR-885-3p expression in T1D patients and to examine the effects of miR-885-3p on the inflammatory response in human monocytes.Methods: Relevant gene expression levels were determined by a quantitative polymerase chain reaction; western blotting and enzyme-linked immunosorbent assays determined the respective protein levels; and the interaction between miRNA and the downstream targets was evaluated using a luciferase reporter assay.Results: MiR-885-3p is down-regulated and the levels of pro-inflammatory cytokines are increased in peripheral blood mononuclear cells (PBMCs) from T1D patients compared to healthy controls. MiR-885-3p overexpression suppressed mRNA expression and secreted protein levels of pro-inflammatory cytokines in THP-1. A luciferase reporter assay showed that miR-885-3p directly targeted the 3'untranslated region of Toll-like receptor 4 (TLR4) and miR-885-3p overexpression down-regulated TLR4 expression in THP-1 cells. The TLR4 mRNA expression level was increased in PBMCs isolated from T1D patients compared to heathy controls.TLR4 overexpression increased the secretion of pro-inflammatory cytokines and enhanced the activity of NF-κB signaling, and also attenuated the inhibitory effects of miR-885-3p overexpression on pro-inflammatory cytokine secretion and the activity of NF-κB signaling in THP-1 cells. Conclusions:The present study identified the down-regulation of miR-885-3p and up-regulation of TLR4 in PBMCs isolated from T1D patients. Further mechanistic data demonstrated that miR-885-3p overexpression represses the production of proinflammatory cytokines via targeting TLR4/NF-κB signaling in THP-1 cells.

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Section: Introductionmentioning

confidence: 97%

“…6 Akerman et al 7 reported that miRNA levels in the serum were correlated with glucose homeostasis and the autoimmunity of islet in T1D patients. Serr et al 8 showed that miR-181a was up-regulated in CD4 + T cells from T1D patients and also that miR-181a/nuclear factor of activated T cells 5 regulated T cell function in the T1D patients.…”

Section: Introductionmentioning

confidence: 99%

MiR‐885‐3p is down‐regulated in peripheral blood mononuclear cells from T1D patients and regulates the inflammatory response via targeting TLR4/NF‐κB signaling

Zhang

Wang

et al. 2019

The Journal of Gene Medicine

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“…In mechanoactivated VSMCs, NFAT5 becomes expressed to drive the expression of gene products that contribute to the remodeling of the ECM and cellular migration, such as tenascin C (TNC) (10,11) and actin b-like 2 (ACTBL2; k-actin), respectively (12). Although originally described as a transcription factor that maintains cellular homeostasis under hypertonicity (13), there is emerging evidence that NFAT5 may, in fact, feature multiple tonicityindependent functions (14), including the control of T-cell tolerance (15), macrophage survival (16), or angiogenesis (17). However, despite the fact that mechanoactivation of VSMCs poses as 1 critical stimulus initiating an extensive adaption of their transcriptome, the relevance of NFAT5 for the outcome of biomechanically induced arterial remodeling processes has not been investigated.…”

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confidence: 99%

Genetic ablation of NFAT5/TonEBP in smooth muscle cells impairs flow‐ and pressure‐induced arterial remodeling in mice

et al. 2018

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The arterial wall adapts to alterations in blood flow and pressure by remodeling the cellular and extracellular architecture. Biomechanical stress of vascular smooth muscle cells (VSMCs) in the media is thought to precede this process and promote their activation and subsequent proliferation. However, molecular determinants orchestrating the transcriptional phenotype under these conditions have been insufficiently studied. We identified the transcription factor, nuclear factor of activated T cells 5 (NFAT5; or tonicity enhancer‐binding protein) as a crucial regulatory element of mechanical stress responses of VSMCs. Here, the relevance of NFAT5 for arterial growth and thickening is investigated in mice upon inducible smooth muscle cell (SMC)‐specific genetic ablation of Nfat5. In cultured mouse VSMCs, loss of Nfat5 inhibits the expression of gene sets involved in the control of the cell cycle and the interaction with the extracellular matrix and cytoskeletal dynamics. In vivo, SMC‐specific knockout of Nfat5 did not affect the general vascular architecture and blood pressure levels under baseline conditions. However, proliferation of VSMCs and the thickening of the arterial wall were inhibited during both flow‐induced collateral remodeling and hypertension‐mediated arterial hypertrophy. Whereas originally described as a hypertonicity‐responsive transcription factor, these findings identify NFAT5 as a novel molecular determinant of biomechanically induced phenotype changes of VSMCs and wall stress‐induced arterial remodeling processes.—Arnold, C., Feldner, A., Zappe, M., Komljenovic, D., De La Torre, C., Ruzicka, P., Hecker, M., Neuhofer, W., Korff, T. Genetic ablation of NFAT5/TonEBP in smooth muscle cells impairs flow‐ and pressure‐induced arterial remodeling in mice. FASEB J. 33, 3364–3377 (2019). http://www.fasebj.org

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“…11,21 Inconsistently, Serr's results showed that blocking miRNA-181a promoted Treg proliferation in murine and humanized models in vivo. 22 Zhou's report also suggested that transfection with miR-181a precursor reduced the Treg numbers in chronic HCV infection. 23 These inconsistent results suggested that miR-181a may exert pro-inflammatory or anti-inflammatory effect in different backgrounds.…”

Section: Discussionmentioning

confidence: 97%

“…miR‐181a is highly expressed in thymocytes, and its abnormal expression impairs both positive and negative thymic selection . Inconsistently, Serr's results showed that blocking miRNA‐181a promoted Treg proliferation in murine and humanized models in vivo . Zhou's report also suggested that transfection with miR‐181a precursor reduced the Treg numbers in chronic HCV infection .…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐181a and microRNA‐155 are involved in the regulation of the differentiation and function of regulatory T cells in allergic rhinitis children

Zeng

Liu

Luo

et al. 2019

Pediatric Allergy Immunology

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Background Regulatory T cells (Tregs) play central roles in limiting airway allergic inflammation and preventing inappropriate Th2 responses to environmental allergens. This study aims to evaluate the role of miR‐181a and miR‐155 in the regulation of the differentiation and function of Tregs through both in vivo and in vitro studies. Methods The CD4+ T cells and Tregs were purified from peripheral blood mononuclear cells (PBMCs) in allergic rhinitis (AR) children, respectively. The miR‐155/181a mimics and inhibitors were transfected into CD4+ T cells and Tregs. The differentiation and function of Tregs were evaluated by flow cytometry and enzyme‐linked immunosorbent assay. AR mice models were established, and miR‐155/181a mimics or inhibitors were injected through tail vein. The Treg percentage and function from mice were compared among different groups. Results The miR‐181a up‐regulated the release of interleukin (IL)‐10 and TGF‐β, whereas the miR‐155 promoted Treg differentiation in CD4+ T cells. Similarly, we also found that miR‐155 promoted Treg proliferation directly through suppressor of cytokine signaling 1 (SOCS1) and sirtuin1 (SIRT1) signaling pathway, whereas miR‐181a up‐regulated mRNA expression of IL‐10 and TGF‐β through phosphatidylinositol 3‐OH kinase (PI3K)/Akt pathway. We also found that miR‐155/181a affect Treg percentage and function in mice model. Conclusion Our findings suggest that miR‐181a and miR‐155 were closely correlated with the proliferation and function of Tregs in AR, providing new potential treatment target.

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A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes

Cited by 49 publications

References 54 publications

MiR‐885‐3p is down‐regulated in peripheral blood mononuclear cells from T1D patients and regulates the inflammatory response via targeting TLR4/NF‐κB signaling

MiR‐885‐3p is down‐regulated in peripheral blood mononuclear cells from T1D patients and regulates the inflammatory response via targeting TLR4/NF‐κB signaling

Genetic ablation of NFAT5/TonEBP in smooth muscle cells impairs flow‐ and pressure‐induced arterial remodeling in mice

MicroRNA‐181a and microRNA‐155 are involved in the regulation of the differentiation and function of regulatory T cells in allergic rhinitis children

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