The zinc transporter Slc30a1 in macrophages plays a protective role against Salmonella infection

The zinc transporter Slc30a1 plays an essential role in maintaining cellular zinc homeostasis; however, its functional role in macrophages remains largely unknown. Here, we systematically examined the expression and function of Slc30a1 in macrophages upon Salmonella infection in both Slc30a1 reporter mice and in macrophage-specific Slc30a1 knockout (Slc30a1fl/flLysMCre) mice. We found that Slc30a1fl/flLysMCremice have an increased susceptibility to Salmonella infection compared to control littermates. Mechanistically, we found that loss of Slc30a1 in macrophages reduced their bactericidal activity via reduced iNOS and NO production due to intracellular zinc accumulation. In addition, we observed significantly increased expression of Mt1 (metallothionein 1) in Salmonella-infected Slc30a1-deficient macrophages, suggesting that Mt1 may serve as a compensatory zinc reservoir. Interestingly, macrophages lacking both Mt1 and Slc30a1 expression (Slc30a1fl/flLysMCre; Mt1-/-) had increased cell death upon Salmonella infection due to excess zinc-induced oxidative stress. Taken together, our results show that Slc30a1 in macrophages can protect against Salmonella infection, providing mechanistic insights into the role of Slc30a1-mediated zinc homeostasis in macrophages in response to infectious disease.