Nonobese diabetic (NOD) mice Congenic for a targeted deletion of 12/15-lipoxygenase are protected from autoimmune diabetes
Nonobese diabetic (NOD) mice Congenic for a targeted deletion of 12/15-lipoxygenase are protected from autoimmune diabetes
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DOI：
10.2337/db07-0830
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发表时间：
2008-01-01
期刊：
影响因子：
7.7
通讯作者：
Nadler, Jerry L.
中科院分区：
文献类型：
--
作者：
McDuffie, Marcia;Maybee, Nelly A.;Nadler, Jerry L.
目的12/15-脂氧合酶（12/15-LO）是脂肪酸氧化还原酶家族中的一员，与多烯脂肪酸反应产生促炎性脂质。12/15-LO在巨噬细胞和胰腺P细胞中表达。它能增强巨噬细胞产生白细胞介素12，其几种产物在体外以纳摩尔浓度诱导P细胞凋亡。我们先前已经证明了12/15-LO在糖尿病链脲佐菌素模型中P细胞损伤中的作用。由于编码12/15-LO的基因由于12/15-LO（基因命名为Alox 15）位于NOD小鼠的Idd 4糖尿病易感性区间内，我们假设12/15-LO也是NOD小鼠糖尿病易感性的关键调节因子。（NOD-Alox 15（null））使用“速度同源”协议，与NOD小鼠相比，12/15-LO缺陷的NITTS-NOD小鼠以显著降低的速率发展糖尿病（30周时，女性为2.5% vs> 60%）。与年龄匹配的非糖尿病NOD雌性小鼠相比，非糖尿病雌性NOD-Alox 15（null）小鼠表现出改善的葡萄糖耐量，以及显著降低的胰岛炎严重程度和改善的P细胞质量。疾病抗性与NOD-Alox 15（null）小鼠4周龄时胰岛浸润活化巨噬细胞数量减少相关，这发生在胰岛炎之前。随后，胰岛相关浸润的特征是CD 4（+）T细胞数量减少和Foxp 3（+）细胞增加。结论-这些结果表明，12/15-LO通过其对巨噬细胞募集或激活的作用，在NOD小鼠中赋予自身免疫性糖尿病易感性中具有重要作用。
OBJECTIVE-12/15-lipoxygenase (12/15-LO), one of a family of fatty acid oxidoreductase enzymes, reacts with polyenoic fatty acids to produce proinflammatory lipids. 12/15-LO is expressed in macrophages and pancreatic P-cells. It enhances interleukin 12 production by macrophages, and several of its products induce apoptosis of P-cells at nanomolar concentrations in vitro. We had previously demonstrated a role for 12/15-LO in P-cell damage in the streptozotocin model of diabetes. Since the gene encoding 12/15-LO (gene designation Alox15) lies within the Idd4 diabetes susceptibility interval in NOD mice, we hypothesized that 12/15-LO is also a key regulator of diabetes susceptibility in the NOD mouse.RESEARCH DESIGN AND METHODS-We developed NOD mice carrying an inactivated 12/15-LO locus (NOD-Alox15(null)) using a "speed congenic" protocol, and the mice were monitored for development of insulitis and diabetes.RESULTS-NOD mice deficient in 12/15-LO develop diabetes at a markedly reduced rate compared with NOD mice (2.5 vs. > 60% in females by 30 weeks). Nondiabetic female NOD-Alox15(null) mice demonstrate improved glucose tolerance, as well as significantly reduced severity of insulitis and improved P-cell mass, when compared with age-matched nondiabetic NOD females. Disease resistance is associated with decreased numbers of islet-infiltrating activated macrophages at 4 weeks of age in NOD-Alox15(null) mice, preceding the development of insulitis. Subsequently, islet-associated infiltrates are characterized by decreased numbers of CD4(+) T cells and increased Foxp3(+) cells.CONCLUSIONS-These results suggest an important role for 12/15-LO in conferring susceptibility to autoimmune diabetes in NOD mice through its effects on macrophage recruitment or activation.