The six-transmembrane protein Stamp2 plays an important role in metabolically 
triggered inflammation and insulin action. We report that Stamp2 is expressed in 
human and mouse macrophages, is regulated upon differentiation or activation, 
acts as an anti-inflammatory protein, and regulates foam cell formation. Absence 
of Stamp2 results in significant increases in cellular NADPH levels, and both 
NADPH homeostasis and the exaggerated inflammatory response of Stamp2(-/-) 
macrophages are rescued by exogenous wild-type but not by a reductase-deficient 
Stamp2 molecule. Chemical and genetic suppression of NADPH production in 
Stamp2(-/-) macrophages reverts the heightened inflammatory response. Stamp2 is 
detected in mouse and human atherosclerotic plaques, and its deficiency promotes 
atherosclerosis in mice. Furthermore, bone marrow transplantation experiments 
demonstrated that Stamp2 in myeloid cells is sufficient to protect against 
atherosclerosis. Our data reveal a role of Stamp2 in controlling intermediary 
metabolites to regulate inflammatory responses in macrophages and in progression 
of atherosclerosis.