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 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 knockout mice compared with wild-type 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 NF-κB signaling. Strikingly, alteration of myeloid cell function resulted in an imbalance of Th17/Th2 responses, which is potentially detrimental to host defense. These results (for the first time, to our knowledge) reveal a vital ZIP8- and Zn-mediated axis that alters the lung myeloid cell landscape and the host response against pneumococcus.

锌 (Zn) 是正常免疫功能和宿主防御所必需的。锌稳态受到锌转运蛋白的严格调节，锌转运蛋白通过锌动员来协调生物过程。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病因。骨髓细胞，包括巨噬细胞和树突状细胞 (DC)，处于宿主防御肺部入侵细菌病原体的前线，并在形成免疫反应的早期发挥着关键作用。细菌感染后，锌转运蛋白 ZIP8 的表达迅速被诱导，并以锌依赖性方式调节骨髓细胞功能。ZIP8 在多大程度上对骨髓细胞功能发挥作用还需要进一步研究。使用一种新型的骨髓特异性Zip8敲除模型，我们确定了 ZIP8 在肺炎球菌感染时的巨噬细胞和 DC 功能中的重要作用。与野生型小鼠相比，将肺炎链球菌注入肺部会导致Zip8敲除小鼠的炎症、发病率和死亡率增加。这与骨髓细胞数量、细胞因子产生和细胞死亡的增加有关。巨噬细胞和 DC 功能的体外分析揭示了细菌刺激后吞噬作用的缺陷和细胞因子产生的增加，部分原因是 NF-κB 信号传导的增加。引人注目的是，骨髓细胞功能的改变导致 Th17/Th2 反应失衡，这可能不利于宿主防御。这些结果（据我们所知，这是第一次）揭示了一个重要的 ZIP8 和 Zn 介导的轴，它改变了肺骨髓细胞景观和宿主对肺炎球菌的反应。