Osteoprotegerin Regulates Pancreatic β-Cell Homeostasis upon Microbial Invasion.
Osteoprotegerin Regulates Pancreatic β-Cell Homeostasis upon Microbial Invasion.
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DOI：
10.1371/journal.pone.0146544
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Matsuo K
中科院分区：
文献类型：
--
作者：
Kuroda Y;Maruyama K;Fujii H;Sugawara I;Ko SB;Yasuda H;Matsui H;Matsuo K
骨保护素（OPG）是核因子-κB配体受体激活剂（RANKL）的诱饵受体，可拮抗RANKL在骨中的破骨细胞生成功能。我们先前证明，全身给予脂多糖（LPS）小鼠外周血中OPG水平升高，RANKL水平降低。在这里，我们发现感染沙门氏菌，葡萄球菌，分枝杆菌或流感病毒的小鼠也显示血清OPG水平升高。然后，我们询问微生物侵入后OPG上调是否对骨外有影响。为此，我们用LPS处理小鼠并观察胰腺中，特别是胰岛β细胞中OPG的产生。在缺乏OPG的小鼠中，LPS给药后的胰岛素释放增强，表明OPG抑制急性炎症条件下的胰岛素分泌。与此一致，在LPS存在下，用OPG处理MIN 6胰腺β细胞减少了葡萄糖刺激后的胰岛素分泌。最后，我们的研究结果表明，LPS诱导的OPG上调部分介导的激活蛋白（AP）-1家族转录因子，特别是Fos蛋白。总的来说，我们报告急性微生物感染升高血清OPG，其通过限制葡萄糖刺激的胰岛素分泌来维持β细胞稳态，可能防止微生物诱导的β细胞分泌能力耗尽。
Osteoprotegerin (OPG), a decoy receptor for receptor activator of NF-κB ligand (RANKL), antagonizes RANKL’s osteoclastogenic function in bone. We previously demonstrated that systemic administration of lipopolysaccharide (LPS) to mice elevates OPG levels and reduces RANKL levels in peripheral blood. Here, we show that mice infected with Salmonella, Staphylococcus, Mycobacteria or influenza virus also show elevated serum OPG levels. We then asked whether OPG upregulation following microbial invasion had an effect outside of bone. To do so, we treated mice with LPS and observed OPG production in pancreas, especially in β-cells of pancreatic islets. Insulin release following LPS administration was enhanced in mice lacking OPG, suggesting that OPG inhibits insulin secretion under acute inflammatory conditions. Consistently, treatment of MIN6 pancreatic β-cells with OPG decreased their insulin secretion following glucose stimulation in the presence of LPS. Finally, our findings suggest that LPS-induced OPG upregulation is mediated in part by activator protein (AP)-1 family transcription factors, particularly Fos proteins. Overall, we report that acute microbial infection elevates serum OPG, which maintains β-cell homeostasis by restricting glucose-stimulated insulin secretion, possibly preventing microbe-induced exhaustion of β-cell secretory capacity.