Metal transporter Slc39a10 regulates susceptibility to inflammatory stimuli by controlling macrophage survival.
Metal transporter Slc39a10 regulates susceptibility to inflammatory stimuli by controlling macrophage survival.
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金属转运蛋白 Slc39a10 通过控制巨噬细胞存活来调节对炎症刺激的敏感性
DOI：
10.1073/pnas.1708018114
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发表时间：
2017-12-05
影响因子：
11.1
通讯作者：
Wang F
中科院分区：
文献类型：
--
作者：
Gao H;Zhao L;Wang H;Xie E;Wang X;Wu Q;Yu Y;He X;Ji H;Rink L;Min J;Wang F
锌对维持免疫系统的完整性是必不可少的，锌稳态受到两个离子转运蛋白家族SLC 39 A和SLC 30 A的严格调节。在世界范围内，估计有20亿人缺锌，这种情况会损害免疫功能，增加对各种感染的易感性。尽管它们在健康和疾病中起着重要作用，但巨噬细胞中锌转运和锌稳态的分子机制仍知之甚少。在这里，我们报告说，SLC 39 A10在巨噬细胞锌稳态中起着至关重要的作用，调节炎症刺激后的免疫反应。具体而言，我们确定了SLC 39 A10在炎症反应期间通过Zn/p53依赖性轴调节巨噬细胞存活中的作用。锌在炎症事件期间控制巨噬细胞功能中起关键作用。细胞锌稳态由两个金属转运蛋白家族调节，即SLC 39 A输入蛋白家族和SLC 30 A输出蛋白家族;然而，这些转运蛋白在维持巨噬细胞功能中的确切作用尚不清楚。使用巨噬细胞特异性Slc 39 a10敲除（Slc 39 a10 fl/fl;LysM-Cre+）小鼠，我们发现Slc 39 a10通过介导响应于LPS刺激的锌稳态在巨噬细胞存活中起重要作用。与Slc 39 a10 fl/fl小鼠相比，Slc 39 a10 fl/fl;LysM-Cre+小鼠在LPS刺激后具有显著更低的死亡率以及减少的肝损伤和更低的循环炎性细胞因子水平。此外，在Slc 39 a10 fl/fl;LysM-Cre+巨噬细胞中降低的细胞内Zn浓度导致p53的稳定，这增加了LPS刺激后的细胞凋亡。伴随的p53敲除在很大程度上挽救了Slc 39 a10 fl/fl;LysM-Cre+小鼠的表型。最后，使用Zn螯合剂TPEN在野生型小鼠中模拟Slc 39 a10 fl/fl;LysM-Cre+小鼠中的表型，并通过Zn补充逆转。综上所述，这些结果表明，Slc 39 a10通过Zn/p53依赖性轴响应于炎症刺激在促进巨噬细胞存活中起作用。
Significance Zn is essential for maintaining the integrity of the immune system, and Zn homeostasis is tightly regulated by two families of ion transporters, SLC39A and SLC30A. Worldwide, an estimated two billion people have Zn deficiency, a condition that can impair immune function and increase susceptibility to a variety of infections. Despite their important roles in health and disease, the molecular mechanisms that underlie Zn transport and Zn homeostasis in macrophages are poorly understood. Here, we report that SLC39A10 plays an essential role in Zn homeostasis in macrophages, regulating the immune response following inflammatory stimuli. Specifically, we identified a role for SLC39A10 in regulating the survival of macrophages via a Zn/p53-dependent axis during the inflammatory response. Zn plays a key role in controlling macrophage function during an inflammatory event. Cellular Zn homeostasis is regulated by two families of metal transporters, the SLC39A family of importers and the SLC30A family of exporters; however, the precise role of these transporters in maintaining macrophage function is poorly understood. Using macrophage-specific Slc39a10-knockout (Slc39a10fl/fl;LysM-Cre+) mice, we found that Slc39a10 plays an essential role in macrophage survival by mediating Zn homeostasis in response to LPS stimulation. Compared with Slc39a10fl/fl mice, Slc39a10fl/fl;LysM-Cre+ mice had significantly lower mortality following LPS stimulation as well as reduced liver damage and lower levels of circulating inflammatory cytokines. Moreover, reduced intracellular Zn concentration in Slc39a10fl/fl;LysM-Cre+ macrophages led to the stabilization of p53, which increased apoptosis upon LPS stimulation. Concomitant knockout of p53 largely rescued the phenotype of Slc39a10fl/fl;LysM-Cre+ mice. Finally, the phenotype in Slc39a10fl/fl;LysM-Cre+ mice was mimicked in wild-type mice using the Zn chelator TPEN and was reversed with Zn supplementation. Taken together, these results suggest that Slc39a10 plays a role in promoting the survival of macrophages through a Zn/p53-dependent axis in response to inflammatory stimuli.
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影响因子：
3.7
作者：
Pyle CJ;Akhter S;Bao S;Dodd CE;Schlesinger LS;Knoell DL
通讯作者：
Knoell DL
影响因子：
20.3
作者：
Gautier, Emmanuel L.;Ivanov, Stoyan;Randolph, Gwendalyn J.
通讯作者：
Randolph, Gwendalyn J.
影响因子：
64.8
作者：
Jiang, Le;Kon, Ning;Li, Tongyuan;Wang, Shang-Jui;Su, Tao;Hibshoosh, Hanina;Baer, Richard;Gu, Wei
通讯作者：
Gu, Wei
影响因子：
15.3
作者：
LEHMANN, V;FREUDENBERG, MA;GALANOS, C
通讯作者：
GALANOS, C
影响因子：
7.2
作者：
Li, Yanhong;Qi, Hongxue;Xiao, Xiangwen
通讯作者：
Xiao, Xiangwen