OBJECTIVE: Recent reports of a proatherogenic phenotype in mice with 
macrophage-specific autophagy deficiency have renewed interest in the role of 
the autophagy-lysosomal system in atherosclerosis. Lysosomes have the unique 
ability to process both exogenous material, including lipids and 
autophagy-derived cargo such as dysfunctional proteins/organelles. We aimed to 
understand the effects of an atherogenic lipid environment on macrophage 
lysosomes and to evaluate novel ways to modulate this system.
APPROACH AND RESULTS: Using a variety of complementary techniques, we show that 
oxidized low-density lipoproteins and cholesterol crystals, commonly encountered 
lipid species in atherosclerosis, lead to profound lysosomal dysfunction in 
cultured macrophages. Disruptions in lysosomal pH, proteolytic capacity, 
membrane integrity, and morphology are readily seen. Using flow cytometry, we 
find that macrophages isolated from atherosclerotic plaques also display 
features of lysosome dysfunction. We then investigated whether enhancing 
lysosomal function can be beneficial. Transcription factor EB (TFEB) is the only 
known transcription factor that is a master regulator of lysosomal biogenesis 
although its role in macrophages has not been studied. Lysosomal stress induced 
by chloroquine or atherogenic lipids leads to TFEB nuclear translocation and 
activation of lysosomal and autophagy genes. TFEB overexpression in macrophages 
further augments this prodegradative response and rescues several deleterious 
effects seen with atherogenic lipid loading as evidenced by blunted lysosomal 
dysfunction, reduced secretion of the proinflammatory cytokine interleukin-1β, 
enhanced cholesterol efflux, and decreased polyubiquitinated protein 
aggregation.
CONCLUSIONS: Taken together, these data demonstrate that lysosomal function is 
markedly impaired in atherosclerosis and suggest that induction of a lysosomal 
biogenesis program in macrophages has antiatherogenic effects.