Critical Role of Zinc Transporter (ZIP8) in Myeloid Innate Immune Cell Function and the Host Response against Bacterial Pneumonia.
Critical Role of Zinc Transporter (ZIP8) in Myeloid Innate Immune Cell Function and the Host Response against Bacterial Pneumonia.
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锌转运蛋白（ZIP 8）在骨髓天然免疫细胞功能和宿主对细菌性肺炎的反应中的关键作用。
DOI：
10.4049/jimmunol.2001395
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发表时间：
2021-09-01
期刊：
影响因子：
--
通讯作者：
Knoell DL
中科院分区：
文献类型：
--
作者：
Hall SC;Smith DR;Dyavar SR;Wyatt TA;Samuelson DR;Bailey KL;Knoell DL
锌（Zn）是正常免疫功能和宿主防御所必需的。锌的动态平衡受到锌转运体的严格调控，锌转运体通过锌的动员协调生物过程。锌缺乏与细菌感染的易感性增加有关，包括肺炎链球菌，这是社区获得性肺炎最常见的原因。骨髓细胞，包括巨噬细胞和树突状细胞（dc），是宿主抵抗肺部细菌病原体入侵的第一线，在形成免疫反应的早期起着关键作用。锌转运蛋白ZIP8的表达在细菌感染后被迅速诱导，并以锌依赖的方式调节髓细胞功能。ZIP8在髓细胞功能中的作用程度有待进一步研究。利用一种新的髓细胞特异性Zip8敲除（KO）模型，我们确定了Zip8在肺炎球菌感染时巨噬细胞和DC功能中的重要作用。与野生型（WT）小鼠相比，将肺炎链球菌注入肺部导致Zip8-KO小鼠的炎症、发病率和死亡率增加。这与骨髓细胞数量增加、细胞因子产生和细胞死亡有关。体外对巨噬细胞和DC功能的分析显示，在细菌刺激下，巨噬细胞吞噬功能出现缺陷，细胞因子产生增加，部分原因是NFκB信号传导增加。引人注目的是，髓细胞功能的改变导致Th17/Th2反应的不平衡，这对宿主防御是潜在的有害的。这些结果首次揭示了一个重要的ZIP8和锌介导的轴，它改变了肺髓细胞景观和宿主对肺炎球菌的反应。
Zinc (Zn) is required for proper immune function and host defense. Zn homeostasis is tightly regulated by Zn transporters that coordinate biological processes through Zn mobilization. Zn deficiency is associated with increased susceptibility to bacterial infections including Streptococcus pneumoniae, the most commonly identified cause of community acquired pneumonia. Myeloid cells, including macrophages and dendritic cells (DCs), are at the front line of host defense against invading bacterial pathogens in the lung and play a critical role early on in shaping the immune response. Expression of the Zn transporter ZIP8 is rapidly induced following bacterial infection and regulates myeloid cell function in a Zn-dependent manner. To what extent ZIP8 is instrumental in myeloid cell function requires further study. Using a novel myeloid-specific, Zip8 knockout (KO) model, we identified vital roles of ZIP8 in macrophage and DC function upon pneumococcal infection. Administration of S. pneumoniae into the lung resulted in increased inflammation, morbidity and mortality in Zip8-KO mice compared to wild type (WT) counterparts. This was associated with increased numbers of myeloid cells, cytokine production, and cell death. In vitro analysis of macrophage and DC function revealed deficits in phagocytosis and increased cytokine production upon bacterial stimulation that was, in part, due to increased NFκB signaling. Strikingly, alteration of myeloid cell function resulted in an imbalance of Th17/Th2 responses, that is potentially detrimental to host defense. These results for the first time reveal a vital ZIP8- and Zn-mediated axis that alters the lung myeloid cell landscape and the host response against pneumococcus.
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DOI：
10.1111/gbb.12690
发表时间：
2020-11
期刊：
Genes, brain, and behavior
影响因子：
--
作者：
Dyavar SR;Potts LF;Beck G;Dyavar Shetty BL;Lawson B;Podany AT;Fletcher CV;Amara RR;Papa SM
通讯作者：
Papa SM
影响因子：
6.7
作者：
Eijkelkamp, Bart A.;Morey, Jacqueline R.;Mcdevitt, Christopher A.
通讯作者：
Mcdevitt, Christopher A.
影响因子：
4.2
作者：
Ibs, KH;Rink, L
通讯作者：
Rink, L
影响因子：
11.8
作者：
File, Thomas M., Jr.;Low, Donald E.;Thye, Dirk
通讯作者：
Thye, Dirk
影响因子：
3.6
作者：
Bayle, Lucie;Chimalapati, Suneeta;Durmort, Claire
通讯作者：
Durmort, Claire