Abstract Body: Dysfunction in macrophage lysosomes resulting in poor handling of atherogenic lipids, apoptotic cells, and other cytotoxic debris leads to progression of atherosclerotic plaque size and complexity. Stimulation of TFEB, the master transcriptional regulator of autophagy-lysosomal biogenesis, in macrophages has been shown to promote the degradative capacity of plaque macrophages with reductions in atherosclerosis. Thus, there is interest in harnessing this pathway for cardiovascular therapeutics. One of the mechanisms by which TFEB is activated and triggered to translocate to the nucleus is the release of calcium from the lysosomal lumen into the cytosol via specialized channels located at the lysosomal membrane that include mucolipin 1 (MCOLN1), also known as the transient receptor potential cation channel mucolipin 1 (TRPML1). We find that TRPML1 is highly expressed in macrophages and is involved in a feedback loop by which TFEB positively regulates TRPML1 mRNA expression to further support long-term autophagy-lysosomal biogenesis. Utilizing a mammalian TRPML agonist, mucolipin synthetic agonist 1 (ML-SA1), we show that induction of lysosomal calcium release can robustly trigger TFEB nuclear translocation in macrophages. In turn, numerous downstream TFEB transcriptional targets mediating autophagy-lysosomal biogenesis are upregulated resulting in salutary effects that include enhanced aggrephagy and clearance of cytotoxic p62-enriched protein aggregates, as well as blunting of inflammasome activation and proinflammatory IL-1β production. Taken together, our data support that stimulation of lysosomal calcium flux can be a novel strategy of enhancing TFEB and macrophage degradative capacity in atherosclerosis