Macrophage activation, which contributes to vascular inflammation, is a central feature of atherosclerotic plaque initiation and development. Gökhan Hotamisligil and his colleagues now identify a new anti-inflammatory mechanism in macrophages that protects against atherosclerosis in mice (Cell Metab. 16, 81–89).

These authors previously showed that the transmembrane protein Stamp2 is needed for normal metabolic homeostasis in mice, including in adipose tissue and liver. In their new work, they show that Stamp2, which was previously characterized as having reductase activity, lowers the amounts of NADPH in macrophages. The increased amounts of NADPH in Stamp2-deficient macrophages led to a proinflammatory phenotype with an increased expression of a host of inflammatory cytokines. Stamp2 deficiency also decreased cholesterol efflux and enhanced foam cell formation. To connect these findings to atherosclerosis, the researchers showed that Stamp2 is expressed in macrophages of atherosclerotic plaques in both humans and mice and that Stamp2 deficiency in mice promoted vascular inflammation and increased the size of atherosclerotic lesions. Stamp2 deficiency only in bone marrow cells also resulted in increased atherosclerotic lesion size, consistent with the idea that Stamp2 acts in macrophages to restrain inflammation and atherosclerosis.