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4261432 
Journal Article 
Metal transporter Slc39a10 regulates susceptibility to inflammatory stimuli by controlling macrophage survival 
Gao, H; Zhao, L; Wang, H; Xie, E; Wang, X; Wu, Q; Yu, Y; He, X; Ji, H; Rink, L; Min, J; Wang, F 
2017 
1 
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
EISSN: 1091-6490 
114 
49 
12940-12945 
English 
29180421 
WOS:000417339700035 
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-specificSlc39a10-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 withSlc39a10
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 inSlc39a10
fl/fl
;LysM-Cre
+
macrophages led to the stabilization of p53, which increased apoptosis upon LPS stimulation. Concomitant knockout ofp53largely rescued the phenotype ofSlc39a10
fl/fl
;LysM-Cre
+
mice. Finally, the phenotype inSlc39a10
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.