Dual oxidases control release of hydrogen peroxide by the gastric epithelium to prevent Helicobacter felis infection and inflammation in mice.
Dual oxidases control release of hydrogen peroxide by the gastric epithelium to prevent Helicobacter felis infection and inflammation in mice.
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DOI：
10.1053/j.gastro.2013.07.011
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发表时间：
2013-11
期刊：
影响因子：
29.4
通讯作者：
Merchant JL
中科院分区：
文献类型：
--
作者：
Grasberger H;El-Zaatari M;Dang DT;Merchant JL
双重氧化酶(DUOX)是一种保守的NADPH氧化酶，在上皮细胞表面产生过氧化氢。DUOX酶由DUOX和DUOXA(DUOX成熟因子)亚基组成。哺乳动物基因组编码2种DUOX同工酶(DUOX1-DUOXA1和DUOX2-DUOXA2)。在细菌感染和胃肠道慢性炎症性疾病期间，这些基因的表达上调。在高等脊椎动物中，DUOX在细胞与微生物相互作用中的作用尚未确定。Duxa1和Duxa2基因突变的小鼠(Duoxa−/−小鼠)和对照组小鼠感染猫咪螺杆菌，建立了幽门螺杆菌感染的模型--幽门螺杆菌是人类最常见的慢性感染。野生型小鼠胃内DUOX2和Duoxa2蛋白表达，DUOX蛋白定位于上皮细胞顶端。多沙−/−小鼠胃内粘液层的定植程度明显高于对照组。增加的定殖率持续到感染的慢性期，并与增加但无效的炎症反应相关。与对照组相比，Duoxa+/−小鼠的H Felis定植也明显增加。我们观察到，与对照组相比，在多沙−/−小鼠中发现的H Felis中过氧化氢诱导的KATA基因的表达减少(P=.0002)，表明DUOX导致这些细菌中的氧化应激。在体外，在H_2O_2的持续水平低至30μM的情况下，H_2O_2诱导的氧化防御未能阻止直接的抑菌作用。根据对Duoxa−/−小鼠的研究，DUOX酶复合体可以防止H Felis的胃定植和炎症反应。这些发现表明，上皮细胞产生的过氧化氢在限制微生物定植方面具有非多余的功能。
Dual oxidases (DUOX) are conserved NADPH oxidases that produce H2O2 at the epithelial cell surface. The DUOX enzyme comprises the DUOX and DUOXA (DUOX maturation factor) subunits. Mammalian genomes encode 2 DUOX isoenzymes (DUOX1–DUOXA1 and DUOX2–DUOXA2). Expression of these genes is upregulated during bacterial infection and chronic inflammatory diseases of the luminal gastrointestinal tract. The roles of DUOX in cellular interactions with microbes have not been determined in higher vertebrates. Mice with disruptions of Duoxa1 and Duoxa2 genes (Duoxa−/− mice) and control mice were infected with Helicobacter felis to create a model of Helicobacter pylori infection—the most common human chronic infection. Infection with H felis induced expression of Duox2 and Duoxa2 in the stomachs of wild-type mice, and DUOX protein specifically localized to the apical surface of epithelial cells. H felis colonized the mucus layer in the stomachs of Duoxa−/− mice to a greater extent than in control mice. The increased colonization persisted into the chronic phase of infection and correlated with an increased, yet ineffective, inflammatory response. H felis colonization was also increased in Duoxa+/− mice, compared with controls. We observed reduced expression of the H2O2-inducible katA gene in H felis that colonized Duoxa−/− mice, compared with that found in controls (P=.0002), indicating that Duox causes oxidative stress in these bacteria. In vitro, induction of oxidative defense by H felis failed to prevent a direct bacteriostatic effect, at sustained levels of H2O2 as low as 30 μM. Based on studies of Duoxa−/− mice, the DUOX enzyme complex prevents gastric colonization by H felis and the inflammatory response. These findings indicate the non-redundant function of epithelial production of H2O2 in restricting microbial colonization.
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1016/j.bbrc.2010.08.037
发表时间：
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影响因子：
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DOI：
10.1083/jcb.201102095
发表时间：
2011-07-11
期刊：
The Journal of cell biology
影响因子：
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作者：
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通讯作者：
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影响因子：
4.8
作者：
De Deken, X;Wang, DT;Miot, F
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