A guanidine-rich regulatory oligodeoxynucleotide improves type-2 diabetes in obese mice by blocking T-cell differentiation

Authors

  • Xiang Cheng,

    Corresponding author
    1. Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology; Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, P. R. China
    2. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
    • Xiang Cheng, Tel: +862785726011; Fax: +862785727340

      Guo-Ping Shi, Tel: +1 6175254358; Fax: +1 6175254380

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    • These authors contributed equally to this work.

  • Jing Wang,

    1. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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    • These authors contributed equally to this work.

  • Ni Xia,

    1. Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology; Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, P. R. China
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  • Xin-Xin Yan,

    1. Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology; Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, P. R. China
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  • Ting-Ting Tang,

    1. Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology; Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, P. R. China
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  • Han Chen,

    1. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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  • Hong-Jian Zhang,

    1. Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology; Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, P. R. China
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  • Juan Liu,

    1. Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology; Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, P. R. China
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  • Wen Kong,

    1. Department of Endocrinology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, P. R. China
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  • Sara Sjöberg,

    1. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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  • Eduardo Folco,

    1. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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  • Peter Libby,

    1. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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  • Yu-Hua Liao,

    1. Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology; Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, P. R. China
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  • Guo-Ping Shi

    Corresponding author
    1. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
    • Xiang Cheng, Tel: +862785726011; Fax: +862785727340

      Guo-Ping Shi, Tel: +1 6175254358; Fax: +1 6175254380

    Search for more papers by this author

Abstract

T lymphocytes exhibit pro-inflammatory or anti-inflammatory activities in obesity and diabetes, depending on their subtypes. Guanidine-rich immunosuppressive oligodeoxynucleotides (ODNs) effectively control Th1/Th2-cell counterbalance. This study reveals a non-toxic regulatory ODN (ODNR01) that inhibits Th1- and Th17-cell polarization by binding to STAT1/3/4 and blocking their phosphorylation without affecting Th2 and regulatory T cells. ODNR01 improves glucose tolerance and insulin sensitivity in both diet-induced obese (DIO) and genetically generated obese (ob/ob) mice. Mechanistic studies show that ODNR01 suppresses Th1- and Th17-cell differentiation in white adipose tissue, thereby reducing macrophage accumulation and M1 macrophage inflammatory molecule expression without affecting M2 macrophages. While ODNR01 shows no effect on diabetes in lymphocyte-free Rag1-deficient DIO mice, it enhances glucose tolerance and insulin sensitivity in CD4+ T-cell-reconstituted Rag1-deficient DIO mice, suggesting its beneficial effect on insulin resistance is T-cell-dependent. Therefore, regulatory ODNR01 reduces obesity-associated insulin resistance through modulation of T-cell differentiation.

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