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

被引:13
作者
Cheng, Xiang [1 ,2 ,3 ,4 ]
Wang, Jing [1 ,2 ]
Xia, Ni [3 ,4 ]
Yan, Xin-Xin [3 ,4 ]
Tang, Ting-Ting [3 ,4 ]
Chen, Han [1 ,2 ]
Zhang, Hong-Jian [3 ,4 ]
Liu, Juan [3 ,4 ]
Kong, Wen [5 ]
Sjoeberg, Sara [1 ,2 ]
Folco, Eduardo [1 ,2 ]
Libby, Peter [1 ,2 ]
Liao, Yu-Hua [3 ,4 ]
Shi, Guo-Ping [1 ,2 ]
机构
[1] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Boston, MA USA
[3] Huazhong Univ Sci & Technol, Lab Cardiovasc Immunol, Union Hosp, Inst Cardiol,Tongji Med Coll, Wuhan 430074, Peoples R China
[4] Minist Educ, Lab Biol Targeted Therapy, Wuhan, Peoples R China
[5] Huazhong Univ Sci & Technol, Dept Endocrinol, Union Hosp, Tongji Med Coll, Wuhan 430074, Peoples R China
基金
中国国家自然科学基金; 美国国家卫生研究院;
关键词
macrophage; obesity; regulatory oligodeoxynucleotide; T-cell differentiation; type-2; diabetes; ADIPOSE-TISSUE INFLAMMATION; SUPPRESSIVE OLIGODEOXYNUCLEOTIDES; BACTERIAL-DNA; GLUCOSE-HOMEOSTASIS; INSULIN-RESISTANCE; ADIPOCYTE SIZE; T(H)17 CELLS; CPG MOTIFS; ACTIVATION; GAMMA;
D O I
10.1002/emmm.201201272
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:1112 / 1125
页数:14
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