The zinc transporter Slc30a1 in macrophages plays a protective role againstSalmonellainfection

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 uponSalmonellainfection in both Slc30a1 reporter mice and in macrophage-specificSlc30a1knockout (Slc30a1^fl/flLysM^Cre) mice. We found thatSlc30a1^fl/flLysM^Cremice have an increased susceptibility toSalmonellainfection 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 ofMt1(metallothionein 1) inSalmonella-infectedSlc30a1-deficient macrophages, suggesting that Mt1 may serve as a compensatory zinc reservoir. Interestingly, macrophages lacking bothMt1andSlc30a1expression (Slc30a1^fl/flLysM^Cre; Mt1^-/-) had increased cell death uponSalmonellainfection due to excess zinc-induced oxidative stress. Taken together, our results show that Slc30a1 in macrophages can protect againstSalmonellainfection, providing mechanistic insights into the role of Slc30a1-mediated zinc homeostasis in macrophages in response to infectious disease.