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标题：Metal transporter Slc39a10 regulates susceptibility to inflammatory stimuli by controlling macrophage survival
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作者：Hong Gao ; Lu Zhao ; Hao Wang 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：49
页码：12940-12945
DOI：10.1073/pnas.1708018114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 ( Slc39a10 ^fl/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 Slc39a10 ^fl/fl mice, Slc39a10 ^fl/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 Slc39a10 ^fl/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 Slc39a10 ^fl/fl ;LysM-Cre ⁺ mice. Finally, the phenotype in Slc39a10 ^fl/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.
关键词：SLC39A10 ; zinc ; macrophage ; ZIP10 ; inflammation