The Toll-Like Receptor Signaling Molecule Myd88 Contributes to Pancreatic Beta-Cell Homeostasis in Response to Injury
The Toll-Like Receptor Signaling Molecule Myd88 Contributes to Pancreatic Beta-Cell Homeostasis in Response to Injury
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DOI：
10.1371/journal.pone.0005063
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发表时间：
2009-04-01
期刊：
影响因子：
3.7
通讯作者：
Nepom, Gerald T.
中科院分区：
文献类型：
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作者：
Bollyky, Paul L.;Bice, Jeffrey B.;Nepom, Gerald T.
在动物模型中，共生菌群和致病微生物影响糖尿病的发生，但对这些相互作用的机制基础知之甚少。我们假设，MyD88是Toll样受体(TLR)途径中的一个接头分子，调节胰岛β细胞功能和体内平衡。我们首先对β细胞进行了组织学检查，发现与C57BL/6对照组相比，MyD88(-/-)小鼠的胰岛较小。然而，MyD88(-/-)小鼠在休息和腹膜内葡萄糖耐量试验(IPGTT)后血糖正常。相比之下，在小剂量链脲佐菌素(STZ)攻击后，MyD88(-/-)小鼠的IPGTT与WT对照组相比出现异常。此外，MyD88(-/-)小鼠的β细胞凋亡增强，肝损伤加重，小剂量STZ治疗后恢复延迟。最后，我们用广谱口服抗生素治疗WT小鼠，以耗尽它们的共生菌群。在WT小鼠中，低剂量口服脂多糖，而不是脂磷酸或抗生素本身，强烈促进血糖控制的增强。这些数据表明，MyD88信号和某些TLR配体主要在损伤的背景下介导对b细胞的动态平衡效应。
Commensal flora and pathogenic microbes influence the incidence of diabetes in animal models yet little is known about the mechanistic basis of these interactions. We hypothesized that Myd88, an adaptor molecule in the Toll-like-receptor (TLR) pathway, regulates pancreatic beta-cell function and homeostasis. We first examined beta-cells histologically and found that Myd88(-/-) mice have smaller islets in comparison to C57Bl/6 controls. Myd88(-/-) mice were nonetheless normoglycemic both at rest and after an intra-peritoneal glucose tolerance test (IPGTT). In contrast, after low-dose streptozotocin (STZ) challenge, Myd88(-/-) mice had an abnormal IPGTT relative to WT controls. Furthermore, Myd88(-/-) mice suffer enhanced beta-cell apoptosis and have enhanced hepatic damage with delayed recovery upon low-dose STZ treatment. Finally, we treated WT mice with broad-spectrum oral antibiotics to deplete their commensal flora. In WT mice, low dose oral lipopolysaccharide, but not lipotichoic acid or antibiotics alone, strongly promoted enhanced glycemic control. These data suggest that Myd88 signaling and certain TLR ligands mediate a homeostatic effect on b-cells primarily in the setting of injury.