Multiple mechanisms involved in diabetes protection by lipopolysaccharide in non-obese diabetic mice.
Multiple mechanisms involved in diabetes protection by lipopolysaccharide in non-obese diabetic mice.
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DOI：
10.1016/j.taap.2015.04.006
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发表时间：
2015-06
影响因子：
3.8
通讯作者：
Jun Wang;H. Cao;Hongjie Wang;Guoxiao Yin;Jiao Du;F. Xia;Jing-li Lu;M. Xiang
中科院分区：
文献类型：
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作者：
Jun Wang;H. Cao;Hongjie Wang;Guoxiao Yin;Jiao Du;F. Xia;Jing-li Lu;M. Xiang
Toll样受体4（TLR 4）的激活被认为对1型糖尿病（T1 D）发展过程中的胰岛细胞炎症和最终β细胞丢失很重要。然而，根据“卫生假说”，细菌内毒素脂多糖（LPS），TLR 4的激动剂，抑制T1 D进展。在这里，我们研究了LPS对非肥胖糖尿病（NOD）小鼠T1 D发展的保护作用的可能机制。我们发现，在糖尿病前期状态下给予NOD小鼠LPS既不能预防也不能逆转胰岛炎，但能延迟发病并降低糖尿病的发病率，而且多次注射方案比单次LPS干预更有效。此外，LPS给药抑制脾T淋巴细胞增殖，增加CD 4 + CD 25 + Foxp 3+调节性T细胞（TCLs）的产生，减少强Th 1促炎细胞因子的合成，并下调TLR 4及其下游MyD 88依赖性信号通路。最重要的是，多次注射LPS诱导具有低TLR 4表达的潜在致耐受性树突状细胞（DC）亚群，而不影响DC表型。将重复LPS处理的NOD小鼠的DC移植到NOD/SCID糖尿病小鼠中，对受体中糖尿病的进展具有持续的保护作用。总之，这些结果表明，多种机制参与了LPS对NOD糖尿病小鼠糖尿病发展的保护作用。这些包括Treg诱导、TLR 4及其下游MyD 88依赖性信号通路的下调以及潜在致耐受性DC亚群的出现。
Toll-like receptor 4 (TLR4) activation has been proposed to be important for islet cell inflammation and eventually β cell loss in the course of type 1 diabetes (T1D) development. However, according to the “hygiene hypothesis”, bacterial endotoxin lipopolysaccharide (LPS), an agonist on TLR4, inhibits T1D progression. Here we investigated possible mechanisms for the protective effect of LPS on T1D development in non-obese diabetic (NOD) mice. We found that LPS administration to NOD mice during the prediabetic state neither prevented nor reversed insulitis, but delayed the onset and decreased the incidence of diabetes, and that a multiple-injection protocol is more effective than a single LPS intervention. Further, LPS administration suppressed spleen T lymphocyte proliferation, increased the generation of CD4+CD25+Foxp3+regulatory T cells (Tregs), reduced the synthesis of strong Th1 proinflammatory cytokines, and downregulated TLR4 and its downstream MyD88-dependent signaling pathway. Most importantly, multiple injections of LPS induced a potential tolerogenic dendritic cell (DC) subset with low TLR4 expression without influencing the DC phenotype. Explanting DCs from repeated LPS-treated NOD mice into NOD/SCID diabetic mice conferred sustained protective effects against the progression of diabetes in the recipients. Overall, these results suggest that multiple mechanisms are involved in the protective effects of LPS against the development of diabetes in NOD diabetic mice. These include Treg induction, down-regulation of TLR4 and its downstream MyD88-dependent signaling pathway, and the emergence of a potential tolerogenic DC subset.