Background:Previous work has demonstrated that the volume-regulated chloride channel is activated during foam cell formation, and inhibition of chloride movement prevents intracellular lipid accumulation. However, the mechanism explaining how chloride movement promotes foam cell formation is not clear.Methods and Results:Foam cell formation was determined by Oil Red O staining. Western blotting and co-immunoprecipitation were used to examine protein expression and protein-protein interaction. Cl−iwas measured using 6-methoxy-N-ethylquinolinium iodide dye. The results showed that Cl−iwas decreased in monocytes/macrophages from patients with hypercholesterolemia and from apoE−/−mice fed with a high-fat diet. Lowering Cl−iupregulated scavenger receptor A (SR-A) expression, increased the binding and uptake of oxLDL, enhanced pro-inflammatory cytokine production and subsequently accelerated foam cell formation in macrophages from humans and mice. In addition, low Cl−solution stimulated the activation of JNK and p38 mitogen-activated protein kinases. Inhibition of JNK and p38 blocked Cl−reduced medium-induced SR-A expression and lipid accumulation. In contrast, reduction of Cl−ipromoted the interaction of SR-A with caveolin-1, thus facilitating caveolin-1-dependent SR-A endocytosis. Moreover, disruption of caveolae attenuated SR-A internalization, JNK and p38 activation, and ultimately prevented SR-A expression and foam cell formation stimulated by low Cl−medium.Conclusions:This data provide strong evidence that reduction of Cl−iis a critical contributor to intracellular lipid accumulation, suggesting that modulation of Cl−iis a novel avenue to prevent foam cell formation and atherosclerosis. (Circ J 2016; 80: 1024–1033)