Beyond knockout: A novel homodimerization-targeting MyD88 inhibitor prevents and cures type 1 diabetes in NOD mice

详细信息    查看全文

• 作者：Xue Zhang^a ; Shuai Xing^a ; ^b ; Mingqiang Li^a ; ^c ; Limin Zhang^a ; Lin Xie^a ; Wentao He^d ; Jianhua Liu^a ; Sheng Chang^a ; Fengchao Jiang^e ; ; Ping Zhou^a ; ^{pzhou@tjh.tjmu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Type 1 diabetes ; Therapeutics ; MyD88 ; MyD88 inhibitor ; DC
• 刊名：Metabolism
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：65
• 期：9
• 页码：1267-1277
• 全文大小：2093 K

文摘

Studies have reported that myeloid differentiation factor 88 (MyD88) plays an important role in the development of type 1 diabetes (T1D). The aim of this study was to determine the effects of the self-created MyD88 inhibitor, TJ-M2010-6, in preventing and treating T1D.

Methods

Molecule docking and co-immunoprecipitation were used to determine the suppressing capability of TJ-M2010-6 on the homodimerization of MyD88. The preventive and therapeutic effects of TJ-M2010-6 were tested in NOD mice.

Results

TJ-M2010-6 interacted with amino acid residues of the MyD88 TIR domain and inhibited MyD88 homodimerization. Continuous administration of TJ-M2010-6 significantly reduced the onset of diabetes during the observation period in NOD mice (36.4% vs. 80%, P < 0.01). Although the immediate TJ-M2010-6 treatment group showed a retardation in the rise of their blood glucose level, the delayed treatment group did not show this effect. Mechanism studies have shown that TJ-M2010-6 treatment significantly inhibits insulitis in vivo. In vitro, TJ-M2010-6 inhibited the maturation of DCs, leading to the suppression of T cell activation and inflammatory cytokine secretion.

Conclusions

These results demonstrated that the strategy targeted at the innate immune system using the MyD88 inhibitor had a profound significance in preventing and treating T1D.