Intestinal alkaline phosphatase detoxifies lipopolysaccharide and prevents inflammation in zebrafish in response to the gut microbiota
Intestinal alkaline phosphatase detoxifies lipopolysaccharide and prevents inflammation in zebrafish in response to the gut microbiota
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DOI：
10.1016/j.chom.2007.10.010
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发表时间：
2007-12-01
影响因子：
30.3
通讯作者：
Guillemin, Karen
中科院分区：
文献类型：
--
作者：
Bates, Jennifer M.;Akerlund, Janie;Guillemin, Karen
脊椎动物在其肠道微生物群中具有丰富的脂多糖（LPS）。碱性磷酸酶可以使LPS的内毒素组分去磷酸化和解毒。在这里，我们表明，表达的斑马鱼肠碱性磷酸酶（lap），定位于肠腔刷状缘，在肠道菌群的建立过程中诱导。lap缺陷型斑马鱼对LPS毒性过敏，并表现出暴露于LPS的野生型斑马鱼的过度肠嗜中性粒细胞内流特征。这两种lap突变体表型都依赖于Myd 88和肿瘤坏死因子受体（Tnfr），这些蛋白质也参与哺乳动物的LIPS敏感性。当无菌饲养时，lap缺陷斑马鱼的肠道缺乏中性粒细胞。总之，这些发现表明内源性微生物群通过涉及lap，Myd 88和Tnfr的过程在斑马鱼肠道中建立了中性粒细胞的正常稳态水平。因此，通过预防炎症反应，lap在促进粘膜对肠道细菌的耐受性方面起着至关重要的作用。
Vertebrates harbor abundant lipopolysaccharide (LPS) in their gut microbiota. Alkaline phosphatases can dephosphorylate and detoxify the endotoxin component of LPS. Here, we show that expression of the zebrafish intestinal alkaline phosphatase (lap), localized to the intestinal lumen brush border, is induced during establishment of the gut microbiota. lap-deficient zebrafish are hypersensitive to LPS toxicity and exhibit the excessive intestinal neutrophil influx characteristic of wild-type zebrafish exposed to LPS. Both of these lap mutant phenotypes are dependent on Myd88 and Tumor Necrosis Factor Receptor (Tnfr), proteins also involved in LIPS sensitivity in mammals. When reared germ-free, the intestines of lap-deficient zebrafish are devoid of neutrophils. Together, these findings demonstrate that the endogenous microbiota establish the normal homeostatic level of neutrophils in the zebrafish intestine through a process involving lap, Myd88, and Tnfr. Thus, by preventing inflammatory responses, lap plays a crucial role in promoting mucosal tolerance to resident gut bacteria.