Cystine/Glutamate antiporter system x(c)(-) deficiency impairs macrophage glutathione metabolism and cytokine production

System x(c)(-), encoded by Slc7a11, is an antiporter responsible for exporting glutamate while importing cystine, which is essential for protein synthesis and the formation of thiol peptides, such as glutathione. Glutathione acts as a co-factor for enzymes responsible for scavenging reactive oxygen species. Upon exposure to bacterial products, macrophages exhibit a rapid upregulation of system x(c)(-). This study investigates the impact of Slc7a11 deficiency on the functionality of peritoneal and bone marrow-derived macrophages. Our findings reveal that the absence of Slc7a11 results in significantly reduced glutathione levels, compromised mitochondrial flexibility, and hindered cytokine production in bone marrow-derived macrophages. Conversely, system x(c)(-) has a lesser impact on peritoneal macrophages in vivo. These results indicate that system x(c)(-) is essential for maintaining glutathione levels, mitochondrial functionality, and cytokine production, with a heightened importance under atmospheric oxygen tension.