Zinc ameliorates intestinal barrier dysfunctions in shigellosis by reinstating claudin-2 and-4 on the membranes
Zinc ameliorates intestinal barrier dysfunctions in shigellosis by reinstating claudin-2 and-4 on the membranes
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DOI：
10.1152/ajpgi.00092.2018
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发表时间：
2019-02-01
影响因子：
4.5
通讯作者：
Hogue, Kazi Mirajul
中科院分区：
文献类型：
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作者：
Sarkar, Paramita;Saha, Tultul;Hogue, Kazi Mirajul
当志贺氏菌等病原体改变上皮通透性时，锌（Zn2+）是否通过调节紧密连接（TJ）蛋白来调节屏障功能尚不清楚。我们研究了Zn2+在体内恢复志贺菌感染小鼠组织和体外T84细胞单层中受损屏障功能的潜在益处。基底外侧志贺氏菌感染引发了经上皮抵抗的时间依赖性下降，随后是fitc标记的葡聚糖的细胞旁渗透性增加和离子选择性改变。这导致离子和水分流失到肠腔。免疫荧光研究显示，在感染后，claudin-2和-4重新分布到细胞内的位置，这些蛋白在细胞质中积累。Zn2+通过将cladin -2和-4重新分配回质膜，以及通过细胞外信号调节激酶（ERK）1/2依赖性调节TJ蛋白的磷酸化状态，改善了这种受干扰的屏障。Zn2+阻止IL-6和IL-8的升高。小鼠志贺氏菌攻击表明，口服补充Zn2+减少志贺氏菌病的多种病理生理症状。Claudin-2和-4易受志贺氏菌感染，导致屏障功能改变，IL-6和IL-8水平升高。补充Zn2+改善了这种屏障功能障碍，以及涉及erk介导的cladin -2和-4磷酸化状态改变的炎症反应。因此，Zn2+可能对炎症性腹泻和志贺氏菌病有潜在的治疗价值。我们的研究探讨了Zn2+是否可以作为减少志贺氏菌诱导的炎症反应和上皮屏障功能障碍的替代策略。我们已经从细胞内信号通路和Zn2+的紧密连接蛋白表达方面定义了一种机制。Claudin-2和-4对志贺氏菌感染敏感，而在Zn2+存在的情况下，它们对感染相关的屏障功能障碍（包括erk介导的claudin磷酸化状态的改变）具有抗性。
Whether zinc (Zn2+) regulates barrier functions by modulating tight junction (TJ) proteins when pathogens such as Shigella alter epithelial permeability is still unresolved. We investigated the potential benefits of Zn2+ in restoring impaired barrier function in vivo in Shigella-infected mouse tissue and in vitro in T84 cell monolayers. Basolateral Shigella infection triggered a time-dependent decrease in transepithelial resistance followed by an increase in paracellular permeability of FITC-labeled dextran and altered ion selectivity. This led to ion and water loss into the intestinal lumen. Immunofluorescence studies revealed redistribution of claudin-2 and -4 to an intracellular location and accumulation of these proteins in the cytoplasm following infection. Zn2+ ameliorated this perturbed barrier by redistribution of claudin-2 and -4 back to the plasma membrane and by modulating the phosphorylation state of TJ proteins t hough extracellular signal-regulated kinase (ERK)1/2 dependency. Zn2+ prevents elevation of IL-6 and IL-8. Mice challenged with Shigella showed that oral Zn2+ supplementation diminished diverse pathophysiological symptoms of shigellosis. Claudin-2 and -4 were susceptible to Shigella infection, resulting in altered barrier function and increased levels of IL-6 and IL-8. Zn2+ supplementation ameliorated this barrier dysfunction, and the inflammatory response involving ERK-mediated change of phosphorylation status for claudin-2 and -4. Thus, Zn2+ may have potential therapeutic value in inflammatory diarrhea and shigellosis.NEW & NOTEWORTHY Our study addresses whether Zn2+ could be an alternative strategy to reduce Shigella-induced inflammatory response and epithelial barrier dysfunction. We have defined a mechanism in terms of intracellular signaling pathways and tight-junction protein expression by Zn2+. Claudin-2 and -4 are susceptible to Shigella infection, whereas in the presence of Zn2+ they are resistant to infection-related barrier dysfunction involving ERK-mediated change of phosphorylation status of claudins.