NADPH oxidase but not myeloperoxidase protects lymphopenic mice from spontaneous infections.
NADPH oxidase but not myeloperoxidase protects lymphopenic mice from spontaneous infections.
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NADPH 氧化酶而非髓过氧化物酶可以保护淋巴细胞减少的小鼠免受自发感染。
DOI：
10.1016/j.bbrc.2007.02.029
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发表时间：
2007
影响因子：
3.1
通讯作者：
Grisham,MatthewB
中科院分区：
文献类型：
--
作者：
Ostanin,DmitryV;Barlow,Shayne;Shukla,Deepti;Grisham,MatthewB
适应性免疫系统在宿主抵御微生物入侵中起着重要的作用。然而，缺乏T细胞和b细胞的小鼠在特定的无病原体条件（SPF）下饲养时，令人惊讶地健康并且很少发生自发感染。本研究的目的是确定吞噬细胞相关的NADPH氧化酶或髓过氧化物酶（MPO）在缺乏T细胞和b细胞的小鼠的宿主防御中起什么作用。为了做到这一点，我们将gp91phox缺陷（gp91 ko）或MPO ko小鼠与重组酶激活基因1 （RAG ko）缺陷小鼠杂交，产生了NADPH氧化酶缺陷或MPO缺陷的淋巴细胞减少小鼠。我们发现在SPF条件下饲养的gp91 ko、MPO ko小鼠和淋巴细胞缺陷的RAG ko小鼠都不会发生自发性感染，所有小鼠的寿命都与野生型（WT）动物相似。相比之下，gp91xRAG双缺陷小鼠（DKO）而非MPOxRAG DKO小鼠在生命早期发生自发性多器官细菌和真菌感染，仅存活数月。gp91xRAG DKO小鼠感染的特征是皮肤、肝脏、心脏、大脑、肾脏和肺部的肉芽肿性炎症。在饮水中添加抗生素可减少自发性感染，提高小鼠存活率。从gp91ko和gp91xRAG DKO小鼠中获得的牡蛎糖原诱导的多形核中性粒细胞（PMNs）和巨噬细胞没有检测到NADPH氧化酶活性，而WT、RAG ko和MPOxRAG DKO小鼠的PMNs和巨噬细胞在对肉豆蔻酸酯的反应中产生大量相似量的超氧化物。gp91xRAG DKO小鼠的死亡率增加不是由于炎症细胞募集或NO合成酶活性（iNOS）的缺陷，因为与WT小鼠相比，这些小鼠中诱导的PMN和巨噬细胞的总数以及PMN和巨噬细胞产生的一氧化氮衍生代谢物的数量相似且没有减少。综上所述，我们的数据表明，淋巴细胞减少小鼠的宿主防御需要NADPH氧化酶，而不需要MPO（也不需要iNOS），淋巴细胞和NADPH氧化酶可以相互弥补彼此的不足，以提供对自发细菌感染的抵抗力。
The adaptive immune system plays an important role in host defense against invading micro-organisms. Yet, mice deficient in T- and B-cells are surprisingly healthy and develop few spontaneous infections when raised under specific pathogen-free conditions (SPF). The objective of this study was to ascertain what role phagocyte-associated NADPH oxidase or myeloperoxidase (MPO) plays in host defense in mice lacking both T- and B-cells. To do this, we generated lymphopenic mice deficient in either NADPH oxidase or MPO by crossing gp91phox-deficient (gp91 ko) or MPO ko mice with mice deficient in recombinase activating gene-1 (RAG ko). We found that neither gp91 ko, MPO ko mice nor lymphocyte-deficient RAG ko mice developed spontaneous infections when raised under SPF conditions and all mice had life spans similar to wild-type (WT) animals. In contrast, gp91xRAG double-deficient (DKO) but not MPOxRAG DKO mice developed spontaneous multi-organ bacterial and fungal infections early in life and lived only a few months. Infections in the gp91xRAG DKO mice were characterized by granulomatous inflammation of the skin, liver, heart, brain, kidney, and lung. Addition of antibiotics to the drinking water attenuated the spontaneous infections and increased survival of the mice. Oyster glycogen-elicited polymorphonuclear neutrophils (PMNs) and macrophages obtained from gp91 ko and gp91xRAG DKO mice had no detectable NADPH oxidase activity whereas WT, RAG ko, and MPOxRAG DKO PMNs and macrophages produced large and similar amounts of superoxide in response to phorbol myristate acetate. The enhanced mortality of the gp91xRAG DKO mice was not due to defects in inflammatory cell recruitment or NO synthase activity (iNOS) as total numbers of elicited PMNs and macrophages as well as PMN- and macrophage-derived production of nitric oxide-derived metabolites in these mice were similar and not reduced when compared to that of WT mice. Taken together, our data suggest that that NADPH oxidase but not MPO (nor iNOS) is required for host defense in lymphopenic mice and that lymphocytes and NADPH oxidase may compensate for each other’s deficiency in providing resistance to spontaneous bacterial infections.